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Inheritance

1

Autosomal Dominant HP:0000006

Heterozygous PCSK9 gain-of-function variants segregate as an autosomal dominant trait, as first shown by linkage of the HCHOLA3 locus at 1p32 in French ADH pedigrees.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:24404629 SUPPORT Human Clinical

"APOB-, LDLR-, and PCSK9-related FH are inherited in an autosomal dominant manner."

GeneReviews states the mode of inheritance for PCSK9-related FH explicitly.

PMID:24404629 SUPPORT Human Clinical

"Each child of an individual with a heterozygous pathogenic variant in APOB, LDLR, or PCSK9 has a 50% chance of inheriting the pathogenic variant and having FH."

GeneReviews states the 50% transmission risk for a heterozygous PCSK9 variant, the recurrence figure used in genetic counselling.

PMID:12730697 SUPPORT Human Clinical

"We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."

The founding report identifies PCSK9 as the third autosomal dominant hypercholesterolemia locus, establishing the disease entity curated here.

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Mechanistic Hypotheses

2

PCSK9-accelerated LDL receptor degradation

ldlr_degradation_model CANONICAL

Evidence balance 1 support

The accepted model: gain-of-function PCSK9 binds the hepatocyte LDL receptor's EGF-A domain, reroutes it to the lysosome, depletes the surface receptor pool, and so reduces hepatic LDL clearance. This model is what PCSK9-directed therapeutics were designed against and what their LDL-C lowering confirms in vivo.

Pathograph links

PCSK9 Gain-of-Function Variant -> Hepatic PCSK9 Synthesis and Secretion DIRECT The variant allele is transcribed and translated in the hepatocyte and the mutant protein is secreted into plasma, where it acts on the LDL receptor. This step is separated out because it is the point at which siRNA therapy acts.

Hepatic PCSK9 Synthesis and Secretion -> PCSK9 Binding to the LDL Receptor EGF-A Domain DIRECT Circulating PCSK9 engages the LDL receptor at the hepatocyte surface; with a gain-of-function allele that engagement destroys more receptor.

PCSK9 Binding to the LDL Receptor EGF-A Domain -> Lysosomal Rerouting and Degradation of the Hepatocyte LDL Receptor DIRECT Bound PCSK9 blocks the acid-dependent conformational change that would normally release the ligand and return the receptor to the surface.

Lysosomal Rerouting and Degradation of the Hepatocyte LDL Receptor -> Reduced Hepatic Clearance of Circulating LDL Particles DIRECT Fewer hepatocyte surface receptors directly reduce receptor-mediated uptake of LDL from plasma.

Reduced Hepatic Clearance of Circulating LDL Particles -> Chronic Elevation of Plasma LDL Cholesterol DIRECT Impaired hepatic removal raises the steady-state plasma LDL concentration.

Show evidence (1 reference)

PMID:17452316 SUPPORT In Vitro

"As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded."

The core mechanistic claim of the canonical model.

Increased hepatic apoB-lipoprotein secretion

apob_secretion_model ALTERNATIVE

Evidence balance 1 support

A competing/superimposed model in which FH-associated PCSK9 variants raise circulating LDL chiefly by increasing secretion of nascent apoB100-containing lipoprotein from the hepatocyte, rather than by depleting the LDL receptor. In the study that proposed it, receptor content was only slightly reduced by D374Y and S127R while apoB secretion rose 2-4 fold. The two models are not mutually exclusive, and the alternative has not displaced the receptor-degradation model as the therapeutic rationale.

Pathograph links

PCSK9 Gain-of-Function Variant -> Increased Hepatic Secretion of ApoB-Containing Lipoproteins INDIRECT KNOWN INTERMEDIATES An alternative, non-mutually-exclusive route by which the same variants may raise circulating LDL - increased secretion of nascent apoB100-containing lipoprotein from the hepatocyte. Intermediates: hepatocyte expression of the mutant PCSK9 protein

Increased Hepatic Secretion of ApoB-Containing Lipoproteins -> Chronic Elevation of Plasma LDL Cholesterol DIRECT Increased output of apoB100 lipoprotein from the liver would raise circulating LDL independently of receptor number.

Show evidence (1 reference)

PMID:15772090 SUPPORT In Vitro

"no differences in LDL-receptor content were observed in cells expressing WT, S386A or F216L PCSK9 and only a small reduction in cells expressing the D374Y or S127R mutants."

The observation that motivates the alternative model - a small receptor effect alongside a large secretion effect in this system.

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Discussions and Knowledge Gaps

1

In human PCSK9 gain-of-function carriers, how much of the LDL-cholesterol elevation is attributable to accelerated LDL receptor degradation versus increased hepatic secretion of apoB100-containing lipoprotein?

KNOWLEDGE GAP OPEN adh3_receptor_degradation_vs_apob_secretion

Attached to

pathophysiology#Increased Hepatic Secretion of ApoB-Containing Lipoproteins pathophysiology#Chronic Elevation of Plasma LDL Cholesterol

Two in vitro systems give opposite emphases for the same PCSK9 variants. Hepatocyte and HepG2 studies show a large fall in cell-surface LDL receptor with D374Y and S127R; McArdle-7777 rat hepatoma cells expressing the same variants show only a small receptor reduction but a 2-4 fold rise in apoB100-lipoprotein secretion. No human in vivo measurement apportions the LDL-C elevation between the two routes. This matters therapeutically: a secretion-dominant contribution would not be neutralised by extracellular PCSK9 blockade, whereas hepatic PCSK9 knockdown would address both.

Proposed experiments

Stable-isotope LDL apoB kinetics in PCSK9 gain-of-function carriers

adh3_ldl_apob_kinetics

Measure LDL apoB100 production rate and fractional catabolic rate by stable-isotope turnover in genotyped PCSK9 gain-of-function heterozygotes versus LDLR-mutation heterozygotes and normolipidemic controls, to partition the LDL-C elevation between overproduction and impaired clearance.

Head-to-head response to extracellular versus intracellular PCSK9 blockade

adh3_mab_vs_sirna_response

Compare LDL-C and apoB kinetic response to a PCSK9 monoclonal antibody (extracellular neutralisation) versus inclisiran (hepatic synthesis knockdown) within the same PCSK9 gain-of-function carriers; a secretion-dominant mechanism predicts a differential response.

Show evidence (1 reference)

PMID:15772090 SUPPORT In Vitro

"no differences in LDL-receptor content were observed in cells expressing WT, S386A or F216L PCSK9 and only a small reduction in cells expressing the D374Y or S127R mutants."

Documents the discrepant receptor result that motivates this gap.

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Pathophysiology

12

PCSK9 Gain-of-Function Variant

A heterozygous germline missense variant in PCSK9 that increases the protein's LDL-receptor-degrading activity. The classical alleles are S127R and F216L (the two variants of the founding French pedigrees) and D374Y (the severe British/Norwegian allele). The variants do not act through a common biochemical route: S127R and D374Y differ sharply in autocatalytic zymogen processing while F216L processes normally, and processing itself does not separate gain- from loss-of-function alleles. What they share is the functional output measured in cells - an excess of receptor-degrading PCSK9 activity.

Increased hepatic apoB-lipoprotein secretion PCSK9-accelerated LDL receptor degradation

PCSK9 hgnc:20001

Genetic context PCSK9 hgnc:20001 allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

The variant consequence is a gain of function: the mutant protein degrades more LDL receptor than wild-type PCSK9 does. This is recorded on the genetic context (the variant), not as a Descriptor modifier, because the claim is about the consequence of a specific allele.

liver UBERON:0002107

Downstream

Hepatic PCSK9 Synthesis and Secretion The variant allele is transcribed and translated in the hepatocyte and the mutant protein is secreted into plasma, where it acts on the LDL receptor. This step is separated out because it is the point at which siRNA therapy acts.

Increased Hepatic Secretion of ApoB-Containing Lipoproteins An alternative, non-mutually-exclusive route by which the same variants may raise circulating LDL - increased secretion of nascent apoB100-containing lipoprotein from the hepatocyte.

Show evidence (2 references)

PMID:12730697 SUPPORT Human Clinical

"PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis."

Identifies the disease gene product as a liver-expressed subtilase acting in cholesterol homeostasis, the substrate of this trigger node.

PMID:24404629 SUPPORT Human Clinical

"The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."

GeneReviews specifies that it is the gain-of-function direction of PCSK9 variation that causes FH, supporting the functional_impact_category here.

Hepatic PCSK9 Synthesis and Secretion

PCSK9 is synthesised in the hepatocyte and secreted into the circulation, where it acts on LDL receptors on the same and other cells. Secreted PCSK9 is sufficient on its own to deplete hepatic LDL receptors, as parabiosis between PCSK9-transgenic and wild-type mice shows. This node is the shared upstream of both the canonical receptor-degradation route and the alternative apoB-secretion route, and it is where hepatic PCSK9 knockdown acts.

PCSK9-accelerated LDL receptor degradation

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

PCSK9 Binding to the LDL Receptor EGF-A Domain Circulating PCSK9 engages the LDL receptor at the hepatocyte surface; with a gain-of-function allele that engagement destroys more receptor.

Show evidence (2 references)

PMID:17080197 SUPPORT Model Organism

"After parabiosis, secreted PCSK9 was transferred to the circulation of wild-type mice and reduced the number of hepatic LDLRs to nearly undetectable levels."

Shows that PCSK9 secreted by the liver acts through the circulation to deplete hepatic LDL receptors, establishing secretion as a distinct and necessary step.

PMID:12730697 SUPPORT Human Clinical

"PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis."

Establishes the liver as the site of PCSK9 expression.

PCSK9 Binding to the LDL Receptor EGF-A Domain

Secreted PCSK9 binds the first epidermal growth factor-like repeat (EGF-A) of the LDL receptor's EGF homology domain at the hepatocyte surface. The interaction is calcium-dependent and its affinity rises steeply as pH falls from 7 to 5.2, so the complex tightens rather than dissociates as the receptor traverses the endosome. The evidence curated on this node is from wild-type recombinant PCSK9 and establishes where and how PCSK9 engages the receptor; the variant-specific excess is curated one node downstream, where it was measured as receptor loss rather than as binding affinity.

PCSK9-accelerated LDL receptor degradation

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Lysosomal Rerouting and Degradation of the Hepatocyte LDL Receptor Bound PCSK9 blocks the acid-dependent conformational change that would normally release the ligand and return the receptor to the surface.

Show evidence (2 references)

PMID:17452316 SUPPORT In Vitro

"Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR."

Localises the PCSK9 binding site on the LDL receptor to the EGF-A repeat.

PMID:17452316 SUPPORT In Vitro

"Binding to EGF-A was calcium-dependent and increased dramatically with reduction in pH from 7 to 5.2."

Establishes the pH dependence that makes the complex persist through endocytosis rather than dissociating in the endosome.

Lysosomal Rerouting and Degradation of the Hepatocyte LDL Receptor

The rate-limiting step of ADH3. Instead of recycling to the plasma membrane, the PCSK9-bound LDL receptor is diverted from the endosome to the lysosome and degraded. The hepatocyte surface receptor pool therefore falls even though the LDLR gene and protein are structurally normal. This is the node that distinguishes ADH3 from LDLR- and APOB-related FH, and it is the node that PCSK9-directed drugs act upstream of.

PCSK9-accelerated LDL receptor degradation

hepatocyte CL:0000182

LDL receptor recycling to the plasma membrane GO:0001881 ↓ DECREASED LDL receptor degradation GO:0032802 ↑ INCREASED

liver UBERON:0002107

Downstream

Reduced Hepatic Clearance of Circulating LDL Particles Fewer hepatocyte surface receptors directly reduce receptor-mediated uptake of LDL from plasma.

Show evidence (3 references)

PMID:17452316 SUPPORT In Vitro

"The addition of PCSK9, but not heat-inactivated PCSK9, to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes."

Demonstrates the plasma-membrane-to-lysosome rerouting that defines this node.

PMID:16571601 SUPPORT In Vitro

"The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."

Quantifies the fall in hepatocyte surface LDL receptor caused specifically by the S127R and D374Y gain-of-function alleles.

PMID:15358785 SUPPORT In Vitro

"The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients."

Shows the surface-receptor deficit in cells taken from S127R patients, not only in transfection models. The measurement is in lymphoblasts rather than hepatocytes, so it evidences the receptor-loss mechanism rather than the hepatic cell-type binding of this node.

Reduced Hepatic Clearance of Circulating LDL Particles

The liver is the principal route by which LDL leaves the circulation. With the hepatocyte receptor pool depleted, receptor-mediated uptake of LDL falls and the plasma residence time of LDL particles lengthens.

PCSK9-accelerated LDL receptor degradation

hepatocyte CL:0000182

receptor-mediated endocytosis of LDL GO:0006898 ↓ DECREASED low-density lipoprotein particle clearance GO:0034383 ↓ DECREASED

liver UBERON:0002107

Experimental models

Urine-derived iPSC hepatocyte-like cells from a PCSK9 S127R carrier (HLC-S127R) IPSC DERIVED MODEL Hepatocyte-like cells carrying the patient's S127R allele take up 71% less LDL than control cells, the cellular readout of this node.

Animal models

D374Y-PCSK9 transgenic Yucatan minipig Pig recapitulates Transgenic pigs show the receptor-depletion-to-clearance-failure step directly, with both hepatic LDL receptor level and LDL clearance measured in the same animals.

Downstream

Chronic Elevation of Plasma LDL Cholesterol Impaired hepatic removal raises the steady-state plasma LDL concentration.

Show evidence (2 references)

PMID:17452316 SUPPORT In Vitro

"Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of hepatic low density lipoprotein receptors (LDLR), the major route of clearance of circulating cholesterol."

States that the hepatic LDL receptor is the major clearance route for circulating cholesterol, which is what this node reports as impaired.

PMID:17080197 SUPPORT Model Organism

"Transgenic mice overexpressing human PCSK9 in liver secreted large amounts of the protein into plasma, which increased plasma LDL cholesterol concentrations to levels similar to those of LDLR-knockout mice."

In vivo demonstration that excess secreted PCSK9 phenocopies loss of the LDL receptor at the level of plasma LDL cholesterol.

Increased Hepatic Secretion of ApoB-Containing Lipoproteins

A curated alternative contribution, not the canonical route. In rat hepatoma cells stably expressing the FH-associated PCSK9 variants, secretion of apoB100-containing lipoprotein rose 2-4 fold while LDL receptor content fell only slightly - the opposite emphasis to the hepatocyte receptor-degradation studies. Whether this contributes materially to the human phenotype, and in which cell context, is unresolved; the node is curated so the competing model is visible rather than lost in prose.

Increased hepatic apoB-lipoprotein secretion

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Chronic Elevation of Plasma LDL Cholesterol Increased output of apoB100 lipoprotein from the liver would raise circulating LDL independently of receptor number.

Show evidence (1 reference)

PMID:15772090 SUPPORT In Vitro

"This suggests that the variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers."

The authors' own statement of the alternative mechanism this node represents.

Chronic Elevation of Plasma LDL Cholesterol

Lifelong elevation of plasma LDL cholesterol from birth. In the best characterised PCSK9 cohort - 13 D374Y carriers from four unrelated British families - pretreatment total cholesterol averaged 13.6 mmol/L, materially higher than in severe LDLR-mutation heterozygotes, and remained higher on statin therapy.

cholesterol homeostasis GO:0042632 ↕ DYSREGULATED

Animal models

AAV-hPCSK9(D374Y) mouse Mouse recapitulates Liver expression of human PCSK9 D374Y produces long-term elevation of serum LDL in three mouse backgrounds.

Downstream

Hypercholesterolemia The node is the mechanistic substrate of the measured phenotype.

Elevated LDL Cholesterol The LDL-C measurement is the direct readout of this node.

Tendon Xanthomas Prolonged cholesterol excess deposits in tendon tissue.

Xanthelasma The same chronic cholesterol excess deposits in periocular skin.

Corneal Arcus The same chronic cholesterol excess deposits at the corneal margin.

Subendothelial Retention of ApoB-Containing Lipoproteins Sustained excess of circulating apoB lipoprotein drives its infiltration and retention in the arterial intima.

Show evidence (1 reference)

PMID:16224054 SUPPORT Human Clinical

"The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8+/-14.7 versus 30.2+/-15.7 years; P=0.003), had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004)"

Quantifies the severity of the cholesterol elevation in PCSK9 D374Y carriers against LDLR-mutation comparators.

Subendothelial Retention of ApoB-Containing Lipoproteins

The ADH3 substitution at the atherogenesis module's retention trigger: the disease-specific driver is the PCSK9-driven LDL/apoB burden, but the initiating event - infiltration and retention of apoB-containing lipoproteins in the arterial intima, followed by their oxidative modification and an inflammatory response - is the conserved one.

vascular endothelial cell CL:0000115

cholesterol homeostasis in the arterial wall GO:0042632 ↕ DYSREGULATED inflammatory response GO:0006954 ↑ INCREASED

tunica intima UBERON:0002523

Downstream

Macrophage Foam Cell Formation Retained, modified apoB lipoprotein is internalised by intimal macrophages.

Show evidence (1 reference)

PMID:26844337 SUPPORT Other

"Arterial injury causes endothelial dysfunction promoting modification of apoB containing lipoproteins and infiltration of monocytes into the subendothelial space."

Describes endothelial dysfunction with modification of retained apoB lipoprotein and monocyte entry, the content of this module node. Evidence source is OTHER because this is a review chapter.

Macrophage Foam Cell Formation

Monocytes recruited into the intima differentiate into macrophages and internalise the modified apoB lipoproteins, becoming lipid-laden foam cells - the hallmark of the fatty streak. Macrophage inflammation then feeds back on lipoprotein oxidation, endothelial activation and further monocyte recruitment.

foam cell (lipid-laden macrophage) CL:0000235

foam cell differentiation GO:0090077 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

tunica intima UBERON:0002523

Downstream

Smooth Muscle Cell Switching and Fibrofatty Plaque Formation Macrophage-derived chemoattractants recruit smooth muscle cells that build the plaque's matrix.

Show evidence (1 reference)

PMID:26844337 SUPPORT Other

"Macrophage inflammation results in enhanced oxidative stress and cytokine/chemokine secretion, causing more LDL/remnant oxidation, endothelial cell activation, monocyte recruitment, and foam cell formation."

Documents the feed-forward inflammatory amplification of foam-cell formation. Evidence source is OTHER because this is a review chapter.

Smooth Muscle Cell Switching and Fibrofatty Plaque Formation

Vascular smooth muscle cells infiltrate the lipid-rich intima, proliferate and secrete extracellular matrix, converting the fatty streak into an organised fibrofatty plaque with a matrix-rich fibrous cap. This is the conserved central effector of the atherogenesis module. The ADH3-specific claim curated here is only that carriers reach clinically manifest coronary atherosclerosis earlier than severe LDLR-mutation heterozygotes; the lesion-level steps are the module's conserved ones and are evidenced from general atherosclerosis sources.

vascular smooth muscle cell CL:0000192

smooth muscle cell proliferation GO:0048661 ↑ INCREASED extracellular matrix organization GO:0030198 ↑ INCREASED

artery UBERON:0001637

Animal models

AAV-hPCSK9(D374Y) mouse Mouse partially recapitulates High-fat-fed AAV-PCSK9(D374Y) mice develop aortic atherosclerotic lesions that progress to macrophage-infiltrated, fibrous-capped plaques.

D374Y-PCSK9 transgenic Yucatan minipig Pig recapitulates The pigs develop spontaneous, progressive atherosclerotic lesions without the extreme dietary manipulation mouse models require, at a scale and pathology closer to human disease.

Downstream

Advanced Atheroma with Necrotic Core and Fibrous Cap Continued lipid accumulation and unresolved inflammation convert the fibrofatty plaque into an advanced, vulnerable atheroma.

Peripheral Arterial Disease The same lumen-narrowing fibrofatty lesion occurring in the limb arteries produces flow-limiting peripheral disease. Attached here rather than to the plaque-rupture node because peripheral arterial disease in this context is chronic stenosis, not an acute thrombotic event - which is why it branches off the stenotic stage in parallel with, not downstream of, the coronary events.

Show evidence (3 references)

PMID:26844337 SUPPORT Other

"Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets."

Establishes smooth-muscle-cell matrix production as the plaque-building step. Evidence source is OTHER because this is a review chapter.

PMID:37595697 SUPPORT Other

"vascular smooth muscle cell phenotypic switching through transdifferentiation and stem/progenitor cell activation resulting in the promotion of inflammation, calcification, and secretion of extracellular matrix, altering fibrous cap structure, and necrotic core growth."

Describes the smooth-muscle phenotypic switch and matrix secretion that the module node names. Evidence source is OTHER because this is a histopathology review.

PMID:16224054 SUPPORT Human Clinical

"and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"

Human evidence that PCSK9 gain-of-function carriers reach clinically manifest coronary atherosclerosis earlier than severe LDLR-mutation heterozygotes, licensing this atherogenesis branch for ADH3.

Advanced Atheroma with Necrotic Core and Fibrous Cap

Macrophage apoptosis and defective efferocytosis enlarge a necrotic lipid core, while matrix loss and collagen degradation thin the overlying fibrous cap, converting a stable plaque into a vulnerable one. Curated as the conserved module stage; no ADH3-specific plaque-histology series is cited.

foam cell (lipid-laden macrophage) CL:0000235

extracellular matrix organization GO:0030198 ↓ DECREASED

artery UBERON:0001637

Downstream

Plaque Rupture, Thrombosis, and Ischemic Events A thinned fibrous cap can rupture and expose thrombogenic material.

Show evidence (1 reference)

PMID:26844337 SUPPORT Other

"leading to increased smooth muscle cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases."

Describes the matrix loss and cap thinning that define the advanced, vulnerable atheroma. Evidence source is OTHER because this is a review chapter.

Plaque Rupture, Thrombosis, and Ischemic Events

Cap rupture exposes thrombogenic plaque material, luminal thrombosis follows, and the resulting coronary occlusion produces the clinical ischemic events - angina and myocardial infarction - that occur more than a decade earlier in PCSK9 gain-of-function carriers than in severe LDLR-mutation heterozygotes.

artery UBERON:0001637

Downstream

Premature Coronary Artery Disease The arterial lesion burden manifests clinically as premature coronary disease.

Myocardial Infarction Acute coronary occlusion produces myocardial infarction.

Angina Pectoris Flow-limiting coronary lesions produce exertional angina.

Show evidence (2 references)

PMID:26844337 SUPPORT Other

"Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE."

States the conserved rupture-thrombosis-ischemia step. Evidence source is OTHER because this is a review chapter.

PMID:16224054 SUPPORT Human Clinical

"and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"

ADH3-specific evidence for the earlier timing of clinically manifest coronary disease at this node.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Cardiovascular 4

Premature Coronary Artery Disease Coronary artery atherosclerosis HP:0001677

Course: PROGRESSIVE

Show evidence (2 references)

PMID:16224054 SUPPORT Human Clinical

"and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"

Quantifies the earlier onset of premature coronary artery disease in PCSK9 D374Y carriers relative to LDLR-mutation heterozygotes.

PMID:17452316 SUPPORT Other

"Gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, whereas loss-of-function mutations result in hypocholesterolemia and protection from heart disease."

Background statement of the established PCSK9 genotype-phenotype relationship, cited only as a secondary corroboration of the PCSK9-carrier cohort finding above. Evidence source is OTHER because the sentence is the paper's framing of prior human genetics, not a result of this in vitro study.

Myocardial Infarction HP:0001658

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as..."

GeneReviews lists myocardial infarction among the premature cardiovascular events of FH, of which PCSK9-related FH is one molecular form.

Angina Pectoris HP:0001681

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as..."

GeneReviews lists angina among the premature cardiovascular events of FH.

Peripheral Arterial Disease Peripheral arterial stenosis HP:0004950

Evidence is from clinically defined FH, not a PCSK9-genotyped cohort. Kept without a `frequency:` band because no PCSK9-specific frequency is available and the FH-wide odds ratios do not translate into one.

Show evidence (1 reference)

PMID:30085243 SUPPORT Human Clinical

"Compared with individuals with unlikely FH, multivariable adjusted ORs (95% CIs) of PAD were 1.84 (1.70 to 2.00) in those with possible FH and 1.36 (1.00 to 1.84) in individuals with probable/definite FH."

Quantifies elevated peripheral arterial disease risk in a general-population FH cohort of 106,172 individuals.

Eye 1

Corneal Arcus HP:0001084

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."

GeneReviews describes early corneal arcus as an FH cholesterol-deposition sign.

Head and Neck 1

Xanthelasma HP:0001114

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."

GeneReviews describes xanthelasma as an FH cholesterol-deposition sign.

Integument 1

Tendon Xanthomas Tendon xanthomatosis HP:0010874

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."

GeneReviews describes tendon xanthomas as an FH cholesterol-deposition sign.

Metabolism 2

Hypercholesterolemia HP:0003124

Temporal: CHRONIC

Show evidence (2 references)

PMID:16224054 SUPPORT Human Clinical

"These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."

Documents severe hypercholesterolemia as the defining clinical phenotype of PCSK9 D374Y carriers.

PMID:19191301 SUPPORT Other

"Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a..."

Attributes hypercholesterolemia to the gain-of-function PCSK9 alleles.

Elevated LDL Cholesterol Increased LDL cholesterol concentration HP:0003141

Temporal: CHRONIC

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"A clinical diagnosis of FH can be established in a proband with characteristic clinical features and significantly elevated LDL-C levels (typically >190 mg/dL in adults and >160 mg/dL in children)."

GeneReviews sets the elevated-LDL-C threshold that defines the biochemical phenotype in PCSK9-related FH as in the other FH genes.

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Genetic Associations

1

PCSK9

Gene: PCSK9 hgnc:20001 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:12730697 SUPPORT Human Clinical

"We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."

Establishes PCSK9 as the causal gene at the HCHOLA3 locus.

PMID:15358785 SUPPORT In Vitro

"The S127R and D374Y mutations result in approximately 50-60% and > or =98% decrease in zymogen processing, respectively."

Supports the allele-level heterogeneity noted above: S127R and D374Y differ markedly from each other in their effect on zymogen processing.

PMID:16554528 SUPPORT Human Clinical

"these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD"

The reciprocal, loss-of-function arm of the same gene: nonsense PCSK9 alleles lower LDL-C and coronary risk lifelong. Cited as mirror-image support for the gain-of-function mechanism asserted in this entry, not as an ADH3 phenotype.

Variants (4)

PCSK9 p.Ser127Arg Pathogenic

Gene: PCSK9 hgnc:20001 missense

One of the two founding ADH3 alleles. Markedly impairs autocatalytic zymogen processing and reduces cell-surface LDL receptor in patient lymphoblasts.

Show evidence (1 reference)

PMID:15358785 SUPPORT In Vitro

"The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients."

Functional consequence of S127R measured in patient-derived cells.

PCSK9 p.Phe216Leu Pathogenic

Gene: PCSK9 hgnc:20001 missense

The second founding ADH3 allele, reported alongside S127R in the original French pedigrees. Zymogen processing is normal, so its gain of function is not explained by the processing defect seen with S127R.

Show evidence (1 reference)

PMID:15358785 SUPPORT In Vitro

"F216L, and R218S natural mutants resulted in normal zymogen processing."

Documents that F216L retains normal zymogen processing.

PCSK9 p.Asp374Tyr Pathogenic

Gene: PCSK9 hgnc:20001 missense

The severe ADH3 allele. Roughly tenfold more potent than wild-type PCSK9 at reducing cell-surface LDL receptor, and associated with a clinical phenotype more severe than severe LDLR-mutation heterozygosity.

Show evidence (2 references)

PMID:17080197 SUPPORT In Vitro

"This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia."

Quantifies the increased receptor-degrading potency of D374Y.

PMID:15772090 SUPPORT Human Clinical

"We have identified the D374Y mutant of PCSK9 in three FH families of English origin; all 12 affected individuals have unusually severe hypercholesterolaemia and require more stringent treatment than typical FH patients, who are heterozygous for defects in the LDL receptor."

Documents the severe clinical phenotype of D374Y carriers.

PCSK9 p.Arg496Trp Pathogenic

Gene: PCSK9 hgnc:20001 missense

A C-terminal cysteine-histidine-rich domain module 1 (CM1) gain-of-function allele. Mechanistically distinct from the three alleles above: rather than altering zymogen processing or receptor affinity directly, it abolishes binding of PCSK9 to LDL particles. Because LDL-bound PCSK9 is less able to degrade the receptor, losing that inhibitory association leaves more free, active PCSK9 - a third route to the same gain of function. Included as a representative of the C-terminal variant class rather than as a well-characterised ADH3 pedigree allele.

Show evidence (2 references)

PMID:36187800 SUPPORT In Vitro

"We previously reported that an R496W GOF mutation in a region of PCSK9 known as cysteine-histidine-rich domain module 1 (CM1) prevents LDL binding in vitro"

Identifies R496W as a CM1-domain gain-of-function allele acting through loss of LDL binding.

PMID:36187800 SUPPORT In Vitro

"Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain."

Establishes loss of LDL association as a shared mechanism spanning two distinct PCSK9 domains, which is what makes this a separate variant class from S127R/F216L/D374Y as classically described.

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Medical Actions

8

Evolocumab

Action: Pharmacotherapy NCIT:C15986

Agent: evolocumab NCIT:C174672

Fully human monoclonal antibody that binds circulating PCSK9 and prevents it from engaging the hepatocyte LDL receptor, restoring receptor recycling and hepatic LDL clearance. In heterozygous familial hypercholesterolemia it lowers LDL cholesterol by approximately 60% on top of statin therapy, and in established atherosclerotic cardiovascular disease it reduces cardiovascular events. It is the mechanistically direct therapy for ADH3: the drug target is the mutated protein itself.

Mechanism Target:

INHIBITS PCSK9 Binding to the LDL Receptor EGF-A Domain — Antibody neutralisation of circulating PCSK9 blocks the EGF-A engagement that initiates receptor degradation.

Show evidence (1 reference)

PMID:28304224 SUPPORT Human Clinical

"Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%."

States the drug's target and its effect on the LDL cholesterol output of this pathway. This is the trial's background statement of the established drug mechanism, cited for the drug-target identity; the trial's own outcome result is cited separately on the treatment.

Show evidence (2 references)

PMID:25282519 SUPPORT Human Clinical

"In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo."

Randomised evidence of efficacy in heterozygous familial hypercholesterolemia, the clinical setting of ADH3.

PMID:28304224 SUPPORT Human Clinical

"In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events."

Outcome evidence that PCSK9 inhibition reduces cardiovascular events, the clinical endpoint this disease threatens.

Alirocumab

Action: Pharmacotherapy NCIT:C15986

Agent: alirocumab NCIT:C174849

Human monoclonal antibody against PCSK9, the same mechanism as evolocumab. In patients with recent acute coronary syndrome on high-intensity statin it reduced recurrent ischemic cardiovascular events.

Mechanism Target:

INHIBITS PCSK9 Binding to the LDL Receptor EGF-A Domain — Antibody binding to circulating PCSK9 prevents the receptor engagement step.

Show evidence (1 reference)

PMID:30403574 SUPPORT Human Clinical

"We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy."

Identifies alirocumab's molecular target as PCSK9. This is the trial's aim sentence rather than a result; it is cited for the drug-target identity only, with the trial's outcome result cited separately on the treatment itself.

Show evidence (1 reference)

PMID:30403574 SUPPORT Human Clinical

"Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo."

Randomised outcome evidence for PCSK9 antibody therapy.

Inclisiran

Action: Pharmacotherapy NCIT:C15986

Agent: inclisiran NCIT:C170062

A small interfering RNA that silences PCSK9 messenger RNA in the hepatocyte, suppressing synthesis of the protein rather than neutralising it after secretion. Given twice yearly after loading. In heterozygous familial hypercholesterolemia it lowered LDL cholesterol by roughly 40% versus baseline (about 48 percentage points versus placebo), with reductions reported across FH genotypes.

Mechanism Target:

INHIBITS Hepatic PCSK9 Synthesis and Secretion — Hepatic silencing of PCSK9 messenger RNA reduces production of the mutant protein itself, acting upstream of its secretion and receptor engagement. This is the one PCSK9-directed mechanism that would also blunt an intracellular (apoB-secretion) contribution.

Show evidence (1 reference)

PMID:32197277 SUPPORT Human Clinical

"In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia."

States inclisiran's mechanism as inhibition of hepatic PCSK9 synthesis. The sentence reports the earlier phase 2 result rather than this trial's own finding, and is cited for the mechanism only; ORION-9's own LDL-C result is cited separately on the treatment.

Show evidence (2 references)

PMID:32197277 SUPPORT Human Clinical

"Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile."

Randomised evidence of efficacy in heterozygous familial hypercholesterolemia.

PMID:32197277 SUPPORT Human Clinical

"There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia."

Reports that the LDL-lowering effect was seen across FH genotypes, the closest available evidence that it applies to PCSK9-gene carriers.

Statin Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: atorvastatin CHEBI:39548 simvastatin NCIT:C29454

HMG-CoA reductase inhibition is first-line lipid-lowering therapy in familial hypercholesterolemia and is the background on which PCSK9-directed agents are added. PCSK9 D374Y carriers respond to statins but remain at substantially higher cholesterol on treatment than LDLR-mutation heterozygotes, which is why they usually need combination therapy.

Mechanism Target:

RESTORES Reduced Hepatic Clearance of Circulating LDL Particles — Statin therapy partially restores hepatic LDL clearance in PCSK9 gain-of-function carriers - serum cholesterol falls, but stays above the level reached by LDLR-mutation heterozygotes on the same drugs.

Show evidence (1 reference)

PMID:16224054 SUPPORT Human Clinical

"had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1+/-3.0 versus 6.5+/-0.9 mmol/L; P=0.006)"

Shows that statin therapy lowers cholesterol in PCSK9 carriers but leaves them above the level reached by LDLR-mutation heterozygotes - partial restoration, hence PARTIAL.

Show evidence (2 references)

PMID:24404629 SUPPORT Human Clinical

"Adults: pharmacotherapy (statins with additional medications as needed) to reduce lipid levels; referral to a lipid specialist if necessary to reduce LDL-C levels"

GeneReviews states statins as first-line pharmacotherapy in FH.

PMID:24404629 SUPPORT Human Clinical

"Children: referral to a lipid specialist; diet and lifestyle modifications; statins can be used in children starting around age eight years."

GeneReviews sets the paediatric starting point for statin therapy, which matters here because the LDL burden is present from birth.

Ezetimibe

Action: Pharmacotherapy NCIT:C15986

Agent: ezetimibe CHEBI:49040

Cholesterol-absorption inhibitor added to statin therapy when the LDL-C target is not reached. It is step two of the standard FH escalation, before a PCSK9-directed agent; it does not act on the PCSK9 lesion itself but lowers the LDL burden the lesion creates.

Mechanism Target:

MODULATES Chronic Elevation of Plasma LDL Cholesterol — Reduced intestinal cholesterol absorption lowers the plasma LDL burden downstream of the PCSK9 lesion rather than correcting it.

Show evidence (1 reference)

PMID:25282519 SUPPORT Human Clinical

"Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol."

Places ezetimibe in the FH treatment sequence while making explicit that statin plus ezetimibe is often not sufficient - hence PARTIAL.

Bempedoic Acid

Action: Pharmacotherapy NCIT:C15986

Agent: bempedoic acid CHEBI:149601

Oral ATP citrate lyase inhibitor that blocks cholesterol synthesis upstream of HMG-CoA reductase. Because it is a prodrug activated by a liver-specific enzyme absent from skeletal muscle, it is the guideline option for patients who cannot tolerate statins - a common situation in FH, where lifelong high-intensity statin therapy is the default. Like statins and ezetimibe it lowers the LDL burden the PCSK9 lesion creates rather than correcting the lesion itself.

Mechanism Target:

MODULATES Chronic Elevation of Plasma LDL Cholesterol — ATP citrate lyase inhibition reduces hepatic cholesterol synthesis and so lowers the circulating LDL burden downstream of the PCSK9 lesion, without acting on PCSK9 or on LDL receptor degradation.

Show evidence (1 reference)

PMID:36876740 SUPPORT Human Clinical

"Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events"

States the molecular target and the LDL-lowering effect that place this agent on the plasma-LDL node rather than on the PCSK9 node.

Show evidence (1 reference)

PMID:36876740 SUPPORT Human Clinical

"The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004)"

CLEAR Outcomes provides the cardiovascular outcome evidence that justifies curating bempedoic acid alongside ezetimibe and apheresis rather than as an investigational option.

LDL Apheresis

Action: therapeutic apheresis Ontology label: Therapeutic Apheresis NCIT:C173286

Extracorporeal removal of apoB-containing lipoproteins from plasma, reserved for carriers whose LDL-C remains dangerously high on maximal drug therapy. Two of the thirteen PCSK9 D374Y carriers in the long-term British follow-up required LDL apheresis (one also partial ileal bypass), which is the most direct evidence available that this severity of intervention is sometimes needed in ADH3 specifically.

Mechanism Target:

MODULATES Chronic Elevation of Plasma LDL Cholesterol — Apheresis removes circulating LDL directly, bypassing the failed hepatic receptor route rather than repairing it.

Show evidence (1 reference)

PMID:16224054 SUPPORT Human Clinical

"or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0+/-1.6 versus 5.4+/-1.0 mmol/L; P=0.001)"

Documents LDL apheresis being used in PCSK9 D374Y carriers as part of the therapy needed to control their cholesterol.

Show evidence (1 reference)

PMID:16224054 SUPPORT Human Clinical

"These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."

Supports escalation to aggressive lipid-lowering management in this genotype, of which apheresis is the most intensive form.

Cardiovascular Risk Factor Modification

Action: lifestyle and risk-factor therapy Ontology label: Lifestyle Therapy NCIT:C15900

Non-pharmacological management: smoking cessation, reduced saturated and trans fat intake, increased soluble fibre, physical activity, weight control, and treatment of hypertension and diabetes. These do not address the PCSK9 lesion but reduce the atherogenic burden it acts upon.

Mechanism Target:

MODULATES Subendothelial Retention of ApoB-Containing Lipoproteins — Risk-factor modification acts on the endothelial-injury and inflammatory arm of atherogenesis rather than on the PCSK9-LDL receptor axis.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."

GeneReviews names the modifiable exposures that aggravate atherosclerotic risk in FH.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking."

GeneReviews management recommendation for primary prevention in FH.

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Environmental Factors

3

High Saturated and Trans Fat Intake

Dietary saturated and trans fat raise circulating LDL on top of the PCSK9-driven clearance defect. This is the one modifiable exposure that acts on the lipid node itself rather than on the vascular outcome, which is why diet is additive to, and never a substitute for, pharmacotherapy in this genotype.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking."

The corresponding dietary recommendation, establishing this as a modifiable exposure in FH management.

Mechanism Target:

EXACERBATES Chronic Elevation of Plasma LDL Cholesterol — Dietary fat intake adds to the circulating LDL burden already produced by the inherited receptor-degradation defect.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."

GeneReviews lists high saturated and trans fat intake among the exposures to avoid in FH, acting at the lipid level itself.

Tobacco Smoking

Smoking does not raise LDL cholesterol, so it acts on the vascular arm rather than on any lipid node. Against a lifetime LDL burden that begins at birth, cessation is disproportionately valuable.

Show evidence (1 reference)

PMID:34433300 SUPPORT Human Clinical

"The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75"

Smoking is retained as one of only seven predictors in a 10-year ASCVD risk score derived prospectively in 3881 heterozygous FH patients. That is the quantitative basis for curating smoking as a modifiable exposure acting on the vascular arm rather than on the lipid node.

Mechanism Target:

EXACERBATES Subendothelial Retention of ApoB-Containing Lipoproteins — Smoking aggravates endothelial dysfunction, the permissive condition for subendothelial lipoprotein retention, without altering the LDL burden.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."

GeneReviews lists smoking first among the exposures to avoid in FH.

Sedentary Lifestyle

Physical inactivity, with the obesity, hypertension and diabetes that accompany it, adds conventional atherosclerotic risk on top of the inherited lipid lesion.

Show evidence (1 reference)

PMID:35294538 SUPPORT Human Clinical

"Among carriers, a favorable lifestyle conferred 86% lower risk of CAD compared with an unfavorable lifestyle (hazard ratio, 0.14 [95% CI, 0.04-0.41])."

In UK Biobank carriers of a monogenic FH variant, a four-component lifestyle score whose components include regular exercise stratified coronary risk steeply. This quantifies physical inactivity as a modifiable exposure in monogenic FH specifically, not only in the general population.

Mechanism Target:

EXACERBATES Subendothelial Retention of ApoB-Containing Lipoproteins — Acts on the vascular arm through the conventional risk factors it promotes, not on the PCSK9-LDL receptor axis.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."

GeneReviews lists sedentary lifestyle among the exposures to avoid in FH.

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Biochemical Markers

2

Plasma LDL Cholesterol

Show evidence (1 reference)

PMID:16224054 SUPPORT Human Clinical

"had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1+/-3.0 versus 6.5+/-0.9 mmol/L; P=0.006)"

Shows serum cholesterol used as the tracked biochemical readout before and during treatment in PCSK9 D374Y carriers.

Plasma Lipoprotein(a)

Show evidence (3 references)

PMID:27185354 SUPPORT Human Clinical

"Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction."

Establishes measurement of lipoprotein(a) as part of the FH workup and its role as a risk modifier.

PMID:27185354 SUPPORT Human Clinical

"High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia"

Supports the confounder role noted above - lipoprotein(a) cholesterol inflates the clinically measured LDL-C used by the phenotypic criteria.

PMID:34433300 SUPPORT Human Clinical

"The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75"

Places lipoprotein(a) among the prognostic variables of a validated FH risk score.

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Diagnosis

3

Molecular Genetic Testing of PCSK9

ADH3 is distinguished from the other dominant forms of familial hypercholesterolemia only by molecular testing; the clinical and biochemical picture overlaps LDLR- and APOB-related FH. Identification of a heterozygous gain-of-function PCSK9 variant establishes the diagnosis and enables cascade screening of relatives.

Show evidence (2 references)

PMID:24404629 SUPPORT Human Clinical

"The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."

GeneReviews states that molecular identification of a gain-of-function PCSK9 variant establishes the molecular diagnosis.

PMID:24404629 SUPPORT Human Clinical

"Genetic testing is the preferred method for clarifying the diagnosis in at-risk family members, when possible."

GeneReviews states that molecular testing is the preferred route for cascade clarification in relatives, the claim made in this entry's description.

Lipid Surveillance from Early Childhood

Because the LDL-C elevation is present from birth, GeneReviews recommends monitoring lipid levels from age two years and identifying modifiable cardiovascular risk factors, so that treatment can start at the point of greatest cumulative benefit.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Surveillance: Monitor lipid levels from age two years; consider noninvasive imaging modalities in adults; identify modifiable risk factors (e.g., smoking, sedentary behavior, hypertension, diabetes, obesity)."

GeneReviews surveillance recommendation for FH.

Clinical Diagnostic Criteria for Familial Hypercholesterolemia

Before molecular testing, patients reach an FH diagnosis through validated phenotypic frameworks - the Dutch Lipid Clinic Network (DLCN), Simon Broome, and MEDPED criteria - which score untreated LDL-C together with tendon xanthomas, corneal arcus, and personal or family history of premature coronary disease. These are FH-wide instruments: they identify a clinical FH phenotype but cannot distinguish ADH3 from LDLR- or APOB-related FH, which is why a positive clinical score is the trigger for the PCSK9 molecular testing curated above rather than a substitute for it. They are also imperfect at predicting a mutation at all, and lipoprotein(a) cholesterol counted inside the measured LDL-C inflates them in a substantial minority of scored patients.

Curated as the FH-wide clinical route into the diagnosis, not as an ADH3-specific instrument. None of DLCN, Simon Broome, or MEDPED contains a gene-level criterion that would separate PCSK9 from LDLR or APOB disease.

Show evidence (2 references)

PMID:29408959 SUPPORT Human Clinical

"To compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED), and American Heart Association (AHA) criteria in predicting an FH-causing mutation."

Names the three clinical criteria sets used to reach an FH diagnosis before genetic testing.

PMID:29408959 SUPPORT Human Clinical

"The DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate."

PARTIAL because the sentence that validates the criteria also records their limitation - only moderate concordance - which is why this entry keeps molecular testing as the diagnostic step.

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Progression

3

Presymptomatic (birth to childhood)

The LDL-cholesterol elevation is present from birth because the variant is constitutional, but carriers are typically asymptomatic in childhood. GeneReviews therefore recommends lipid monitoring from age two years and permits statin therapy from around age eight.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"Surveillance: Monitor lipid levels from age two years; consider noninvasive imaging modalities in adults; identify modifiable risk factors (e.g., smoking, sedentary behavior, hypertension, diabetes, obesity)."

Establishes early-childhood lipid surveillance, which implies the biochemical phenotype precedes any clinical manifestation.

Cholesterol deposition and clinical presentation (young adulthood)

In the long-term British D374Y series, carriers presented about a decade earlier than severe LDLR-mutation heterozygotes, at a mean age of about 21 years, with markedly higher pretreatment cholesterol.

Show evidence (1 reference)

PMID:16224054 SUPPORT Human Clinical

"The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8+/-14.7 versus 30.2+/-15.7 years; P=0.003)"

Quantifies the age at presentation in a PCSK9 gain-of-function cohort.

Premature atherosclerotic cardiovascular disease (adulthood)

Clinically manifest coronary artery disease occurred more than ten years earlier in the PCSK9 D374Y carriers than in severe LDLR-mutation heterozygotes.

Show evidence (1 reference)

PMID:16224054 SUPPORT Human Clinical

"and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"

Quantifies the age at onset of premature coronary disease in this genotype.

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Prevalence

1

Molecularly characterised familial hypercholesterolemia cohorts

Unknown Unknown

No population prevalence estimate specific to PCSK9-related FH is recorded here. PCSK9 gain-of-function is consistently described as the rarest of the three dominant FH genes, but the reported share of solved FH varies widely with cohort ascertainment and sequencing strategy, and a single defensible number could not be sourced from a quotable abstract. Deliberately left as UNKNOWN rather than estimated - see the curation SOP on frequency qualifiers needing their own evidence.

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Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Hypercholesterolemia 3:

Familial hypercholesterolemia due to LDLR variants

Overlapping Features The most common dominant FH form. Clinically indistinguishable from ADH3 at the bedside; distinguished by molecular testing. Mechanistically the receptor itself is defective, rather than being degraded prematurely by a normal-but-overactive regulator.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."

GeneReviews lists LDLR alongside PCSK9 as an alternative molecular cause of the same clinical picture, which is what makes it a differential.

Familial defective apolipoprotein B-100 (APOB)

Overlapping Features Dominant FH caused by APOB variants that impair binding of LDL to the LDL receptor. The receptor and its regulation are intact; the ligand is defective.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."

GeneReviews specifies the APOB mechanism (impaired binding of LDL-C to the receptor) that distinguishes it from PCSK9 gain of function.

Autosomal recessive hypercholesterolemia (LDLRAP1)

Overlapping Features Caused by biallelic LDLRAP1 variants affecting the adaptor required for receptor endocytosis; recessive rather than dominant inheritance.

Show evidence (1 reference)

PMID:24404629 SUPPORT Human Clinical

"LDLRAP1-related FH is caused by biallelic pathogenic variants and is inherited in an autosomal recessive manner."

GeneReviews states the recessive inheritance that separates this entity from dominant ADH3.

Polygenic hypercholesterolemia

Overlapping Features Elevated LDL cholesterol from the aggregate effect of many common small-effect alleles rather than a single dominant variant; the commonest explanation for a clinical FH phenotype without an identified monogenic cause.

Sterol storage disorders presenting with tendon xanthomas

Overlapping Features Sitosterolemia (ABCG5/ABCG8) and cerebrotendinous xanthomatosis (CYP27A1) both produce tendon xanthomas indistinguishable on inspection from those of FH, and lysosomal acid lipase deficiency likewise causes dyslipidaemia with lipid deposition. They are separated from ADH3 not by the xanthomas but by the sterol profile and by inheritance - both are recessive, and in cerebrotendinous xanthomatosis cholesterol may be normal while cholestanol accumulates. This matters here because tendon xanthomatosis is a curated phenotype of this entry and is one of the strongest predictors in the clinical FH criteria above, so a xanthoma phenocopy can score as clinical FH while carrying no PCSK9 variant.

Show evidence (1 reference)

PMID:27678445 SUPPORT Human Clinical

"Tendon xanthoma are most commonly associated with Familial Hypercholesterolemia, but the differential diagnosis includes sitosterolemia and cerebrotendinous xanthomatosis (CTX)."

Names the two sterol storage disorders that phenocopy the tendon-xanthoma sign of FH.

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Related Datasets

1

Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia geo:GSE75545

Microarray expression data from urine-derived iPSC lines and hepatocyte-like cells of a PCSK9 S127R autosomal dominant hypercholesterolemia carrier, a PCSK9 loss-of-function (familial hypobetalipoproteinemia) carrier, and controls. Manually relevance-triaged: the series is about PCSK9-mediated ADH by name and genotype, not merely about the PCSK9 gene.

human MICROARRAY

PMID:26586530

Surfaced by `just discover-datasets` as a DIRECT candidate and confirmed against the linked publication before inclusion. Carries no `evidence:` block by the dataset-curation SOP.

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Clinical Trials

4

NCT01763918 PHASE_III COMPLETED

RUTHERFORD-2: randomised, double-blind, placebo-controlled trial of evolocumab in adults with heterozygous familial hypercholesterolemia on stable lipid-lowering therapy.

Target Phenotypes: Increased LDL cholesterol concentration HP:0003141

Show evidence (1 reference)

clinicaltrials:NCT01763918 SUPPORT Human Clinical

"The primary objective was to evaluate the effect of 12 weeks of evolocumab subcutaneously once every 2 weeks (Q2W) and once monthly (QM), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in adults with heterozygous familial hypercholesterolemia (HeFH)."

Registration record establishing the trial's population (heterozygous FH) and LDL-C endpoint.

NCT05398029 PHASE_I RECRUITING

VT-1001 (VERVE-101): open-label phase 1b single-ascending-dose study of a liver-directed base editor designed to disrupt PCSK9 expression, in heterozygous familial hypercholesterolemia with atherosclerotic cardiovascular disease. Included because it targets the PCSK9 node of this disease's pathograph directly; it is an early-phase safety study, not evidence of efficacy.

Target Phenotypes: Increased LDL cholesterol concentration HP:0003141

Show evidence (1 reference)

clinicaltrials:NCT05398029 SUPPORT Human Clinical

"VERVE-101 uses base-editing technology designed to disrupt the expression of the PCSK9 gene in the liver and lower circulating PCSK9 and LDL-C in patients with established ASCVD due to HeFH."

Registration record establishing that the intervention acts on hepatic PCSK9 expression, the mechanism node of this entry.

NCT03397121 PHASE_III COMPLETED

ORION-9: placebo-controlled, double-blind, randomised trial of twice-yearly inclisiran sodium in adults with heterozygous familial hypercholesterolemia and elevated LDL cholesterol.

Target Phenotypes: Increased LDL cholesterol concentration HP:0003141

Show evidence (1 reference)

clinicaltrials:NCT03397121 SUPPORT Human Clinical

"This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran."

Registration record establishing the trial's population and the intervention relevant to this disease.

NCT05465278 PHASE_IV COMPLETED

ARCHITECT: open-label multicentre study of alirocumab in molecularly diagnosed familial hypercholesterolemia from the SAFEHEART registry, with coronary CT angiography assessment of plaque volume, architecture, and composition. Included specifically because its cohort is genetically confirmed rather than clinically defined, which is the caveat the treatment entries in this file repeatedly flag; and because its endpoint is atherosclerotic plaque - the pathophysiology nodes downstream of the LDL node - rather than LDL-C alone.

Target Phenotypes: Coronary artery atherosclerosis HP:0001677

Show evidence (1 reference)

clinicaltrials:NCT05465278 SUPPORT Human Clinical

"clinical trial to evaluate the effect of alirocumab on the volume, architecture and composition of atherosclerotic plaque in patients with Familial hypercholesterolemia from the SAFEHEART Registry"

Registration record establishing the intervention, the plaque endpoint, and the registry-based FH cohort.

🧫

Experimental Models

1

Urine-derived iPSC hepatocyte-like cells from a PCSK9 S127R carrier (HLC-S127R) IPSC_DERIVED_MODEL

Human induced pluripotent stem cells reprogrammed from urine-derived somatic cells of an individual carrying the ADH3 allele PCSK9 S127R, differentiated into hepatocyte-like cells. The model reproduces the patient's own genotype in the disease-relevant cell type and reads out the functional consequence directly as LDL uptake.

Organism

human NCBITaxon:9606

Cell source

Patient-derived (urine somatic cells reprogrammed to iPSC)

Culture

Two-dimensional hepatocyte-like cell differentiation

Publication

PMID:26586530

Pathograph links

Reduced Hepatic Clearance of Circulating LDL Particles recapitulates fidelity: moderate Hepatocyte-like cells carrying the patient's S127R allele take up 71% less LDL than control cells, the cellular readout of this node.

Limitations: Hepatocyte-like cells derived from iPSC are immature relative to adult hepatocytes; the comparison is between individuals rather than between isogenic corrected and uncorrected lines, so donor background is not controlled.

Readouts

LDL uptake by hepatocyte-like cells

Direction: DECREASED

Interpretation: Direct cellular measurement of the impaired LDL clearance this node asserts.

Show evidence (1 reference)

PMID:26586530 SUPPORT In Vitro

"cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake"

Reports the LDL-uptake measurement grounding this readout.

Show evidence (1 reference)

PMID:26586530 SUPPORT In Vitro

"We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL."

States the model's purpose as a model of PCSK9-mediated autosomal dominant hypercholesterolemia.

The same study reports that pravastatin increased LDL uptake more in HLC-S127R than in control cells, matching the good statin response of the S127R carriers in the corresponding family - a rare instance of an in vitro model tracking a genotype-specific clinical treatment response.

Show evidence (1 reference)

PMID:26586530 SUPPORT In Vitro

"urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function."

The authors' conclusion on the model's utility for studying PCSK9 variant function.

🐁

Animal Models

2

AAV-hPCSK9(D374Y) mouse

A single systemic AAV injection delivers the human D374Y gain-of-function allele to mouse liver, producing sustained hyperlipidaemia and, on a high-fat diet, aortic atherosclerotic lesions with macrophage infiltration and fibrous cap formation. Because the disease allele is the human one and is expressed in the correct organ, this model reproduces the ADH3 mechanism rather than merely a hypercholesterolaemic state.

Species

Mouse

Genotype

Liver-directed AAV transfer of human PCSK9 p.Asp374Tyr into wild-type mice

Background

C57BL/6J, 129/SvPasCrlf, or FVB/NCrl

Genes

PCSK9 hgnc:20001

Publication

PMID:25341796

Pathograph links

Chronic Elevation of Plasma LDL Cholesterol recapitulates fidelity: moderate Liver expression of human PCSK9 D374Y produces long-term elevation of serum LDL in three mouse backgrounds.

Limitations: Expression is achieved by somatic AAV transfer in adult animals rather than by a germline heterozygous allele from conception, so the lifelong "cholesterol-years" exposure central to the human disease is not reproduced; a high-fat diet is required for lesion development.

Readouts

Serum low-density lipoprotein

Direction: INCREASED

Interpretation: Direct biochemical correlate of the human LDL-C elevation node.

Show evidence (1 reference)

PMID:25341796 SUPPORT Model Organism

"mice in the C57BL/6J, 129/SvPasCrlf, or FVB/NCrl backgrounds developed long-term hyperlipidemia with a strong increase in serum low-density lipoprotein."

Reports the LDL measurement grounding this readout.

Show evidence (1 reference)

PMID:25341796 SUPPORT Model Organism

"We aimed to stably express the pathological human D374Y gain-of-function mutant form of PCSK9 (PCSK9(DY)) in adult wild-type mice to generate a hyperlipidemic and proatherogenic animal model, achieved with a single systemic injection with adeno-associated virus (AAV)."

States that the model expresses the human ADH3 disease allele to reproduce the hyperlipidaemic, proatherogenic state.

Smooth Muscle Cell Switching and Fibrofatty Plaque Formation partially recapitulates fidelity: moderate High-fat-fed AAV-PCSK9(D374Y) mice develop aortic atherosclerotic lesions that progress to macrophage-infiltrated, fibrous-capped plaques.

Limitations: Mouse atherosclerosis reproduces lesion initiation and fibrous-cap formation but not the late human complications of plaque rupture and thrombosis; lesions are aortic rather than coronary, and a high-fat diet is required.

Readouts

Aortic atherosclerotic lesion burden and fibrous cap formation

Direction: INCREASED

Interpretation: Histological correlate of the fibrofatty plaque node.

Show evidence (1 reference)

PMID:25341796 SUPPORT Model Organism

"Advanced lesions in these high-fat-diet-fed mice also showed evidence of macrophage infiltration and fibrous cap formation."

Reports the histological lesion features grounding this readout.

Show evidence (1 reference)

PMID:25341796 SUPPORT Model Organism

"Macroscopic and histological analysis showed atherosclerotic lesions in the aortas of AAV-PCSK9(DY) mice fed a high-fat-diet."

Establishes that the model develops atherosclerotic lesions attributable to the PCSK9 D374Y allele.

Show evidence (1 reference)

PMID:25341796 SUPPORT Model Organism

"Single intravenous AAV-PCSK9(DY) injection is a fast, easy, and cost-effective approach, resulting in rapid and long-term sustained hyperlipidemia and atherosclerosis."

The authors' summary of what the model produces, supporting its use as a model of PCSK9 gain-of-function hypercholesterolemia and atherosclerosis.

D374Y-PCSK9 transgenic Yucatan minipig

Cloned Yucatan minipigs expressing human D374Y-PCSK9 in liver show reduced hepatic LDL receptor levels, impaired LDL clearance, severe hypercholesterolaemia, and spontaneous progressive atherosclerosis at a body size that permits intravascular imaging. The model covers the ADH3 chain from hepatic receptor loss through to arterial lesion formation; the late human events of plaque rupture and atherothrombosis are not demonstrated in it.

Species

Pig

Genotype

Liver-specific expression of human PCSK9 p.Asp374Tyr (Sleeping Beauty transposition, somatic cell nuclear transfer)

Background

Yucatan minipig

Genes

PCSK9 hgnc:20001

Publication

PMID:23283366

Pathograph links

Reduced Hepatic Clearance of Circulating LDL Particles recapitulates fidelity: high Transgenic pigs show the receptor-depletion-to-clearance-failure step directly, with both hepatic LDL receptor level and LDL clearance measured in the same animals.

Limitations: The human allele is expressed from a transgene under a liver-specific promoter rather than from the endogenous porcine locus, so expression level and regulation need not match a human heterozygote.

Readouts

Hepatic LDL receptor level

Direction: DECREASED

Interpretation: Confirms that the transgene depletes the hepatic receptor pool in vivo.

Show evidence (1 reference)

PMID:23283366 SUPPORT Model Organism

"D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."

Reports the receptor-level and clearance measurements grounding this readout.

Show evidence (1 reference)

PMID:23283366 SUPPORT Model Organism

"Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9."

Describes the construction of the model on the human ADH3 allele.

Smooth Muscle Cell Switching and Fibrofatty Plaque Formation recapitulates fidelity: high The pigs develop spontaneous, progressive atherosclerotic lesions without the extreme dietary manipulation mouse models require, at a scale and pathology closer to human disease.

Limitations: Even in this model the late human events of plaque rupture and atherothrombosis are not established; lesion progression, not acute coronary syndrome, is what is demonstrated.

Readouts

Progressive atherosclerotic lesion development on noninvasive imaging

Direction: INCREASED

Interpretation: Imaging correlate of arterial plaque formation driven by the PCSK9 gain-of-function allele.

Show evidence (1 reference)

PMID:23283366 SUPPORT Model Organism

"spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."

Reports the imaging readout of lesion progression.

Show evidence (1 reference)

PMID:23283366 SUPPORT Model Organism

"D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans."

States the human disease claim the model was built to reproduce, supporting its relevance to this atherogenesis node.

Show evidence (1 reference)

PMID:23283366 SUPPORT Model Organism

"This model should prove useful for several types of translational research in atherosclerosis."

The authors' own framing of the model's translational scope, supporting its inclusion as an informative model of this disease.

{ }

Source YAML

click to show

name: Autosomal Dominant Hypercholesterolemia 3
creation_date: "2026-08-18T00:00:00Z"
description: >
  Autosomal dominant hypercholesterolemia 3 (ADH3; FH3; HCHOLA3) is the
  PCSK9-related form of familial hypercholesterolemia. Proprotein convertase
  subtilisin/kexin type 9 (PCSK9) is a liver-secreted protein that binds the
  epidermal growth factor-like repeat A (EGF-A) of the low-density lipoprotein
  receptor (LDLR) at the hepatocyte surface and, after co-internalisation,
  reroutes the receptor from the recycling endosome to the lysosome for
  degradation. Heterozygous gain-of-function missense variants in PCSK9
  (classically S127R, F216L and D374Y) intensify this normal regulatory
  activity, so hepatocyte surface LDLR is destroyed faster than it is
  replaced. Fewer receptors means reduced hepatic clearance of circulating
  LDL particles, lifelong elevation of plasma LDL cholesterol, and accelerated
  atherogenesis with premature coronary artery disease; carriers also develop
  the classic cholesterol-deposition stigmata of familial hypercholesterolemia
  (tendon xanthomas, xanthelasma, corneal arcus).

  ADH3 is the rarest of the three dominant FH genes, accounting for a small
  minority of molecularly solved FH, but it is mechanistically distinctive:
  the defect is not in the receptor or its ligand but in a *regulator* of
  receptor abundance, and the receptor pathway itself remains intact. That
  distinction is the direct rationale for PCSK9-directed therapy - the
  monoclonal antibodies evolocumab and alirocumab, which neutralise
  circulating PCSK9, and the small interfering RNA inclisiran, which
  suppresses its hepatic synthesis. The mirror-image loss-of-function PCSK9
  alleles cause low LDL cholesterol and protection from coronary heart
  disease; that protective arm is a separate phenotype and is noted here only
  as the human genetic validation of the drug target, not as part of this
  disease.
category: Mendelian
disease_term:
  preferred_term: Autosomal Dominant Hypercholesterolemia 3
  term:
    id: MONDO:0011369
    label: hypercholesterolemia, autosomal dominant, 3
synonyms:
- HCHOLA3
- FH3
- hypercholesterolemia, autosomal dominant, type 3
- hypercholesterolemia, familial, 3
- PCSK9 familial hypercholesterolemia
- familial hypercholesterolemia caused by mutation in PCSK9
parents:
- Familial Hypercholesterolemia
references:
- reference: PMID:24404629
  title: "Familial Hypercholesterolemia."
  tags:
  - GeneReviews
notes: >-
  Scope decision: curated as a standalone entry rather than a subtype of
  kb/disorders/Familial_Hypercholesterolemia.yaml (MONDO:0005439). Three
  reasons. (1) The FH umbrella entry's subtype axis is *zygosity* (HeFH /
  HoFH), not gene, so ADH3 has no place on it without mixing two orthogonal
  axes. (2) MONDO models MONDO:0011369 as a distinct is_a child of
  MONDO:0005439 defined by its causal gene (RO:0004003 HGNC:20001). (3) The
  mechanism is genuinely distinct: LDLR and APOB forms damage the receptor or
  its ligand, whereas ADH3 leaves both intact and instead accelerates
  regulated destruction of the receptor - which is precisely the mechanism
  PCSK9-inhibitor therapy addresses.

  Named Entity Confusion preflight (dismech NEC SOP): the hypercholesterolemia
  series (FH1/LDLR, familial defective apoB-100/APOB, ADH3/PCSK9) is a
  high-NEC-risk numbered-and-lettered class. Identity anchors were confirmed
  against MONDO before curation - causal gene PCSK9 (HGNC:20001) via
  RO:0004003, OMIM:603776, synonym HCHOLA3. Every mechanistic and genetic
  claim in this entry is anchored on a PCSK9 publication; no LDLR- or
  APOB-specific content has been imported.
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous PCSK9 gain-of-function variants segregate as an autosomal
    dominant trait, as first shown by linkage of the HCHOLA3 locus at 1p32 in
    French ADH pedigrees.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APOB-, LDLR-, and PCSK9-related FH are inherited in an autosomal dominant manner."
    explanation: GeneReviews states the mode of inheritance for PCSK9-related FH explicitly.
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with a heterozygous pathogenic variant in APOB, LDLR, or PCSK9 has a 50% chance of inheriting the pathogenic variant and having FH."
    explanation: >-
      GeneReviews states the 50% transmission risk for a heterozygous PCSK9
      variant, the recurrence figure used in genetic counselling.
  - reference: PMID:12730697
    reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."
    explanation: >-
      The founding report identifies PCSK9 as the third autosomal dominant
      hypercholesterolemia locus, establishing the disease entity curated here.
prevalence:
- population: Molecularly characterised familial hypercholesterolemia cohorts
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence estimate specific to PCSK9-related FH is recorded
    here. PCSK9 gain-of-function is consistently described as the rarest of the
    three dominant FH genes, but the reported share of solved FH varies widely
    with cohort ascertainment and sequencing strategy, and a single defensible
    number could not be sourced from a quotable abstract. Deliberately left as
    UNKNOWN rather than estimated - see the curation SOP on frequency
    qualifiers needing their own evidence.
progression:
- phase: Presymptomatic (birth to childhood)
  notes: >-
    The LDL-cholesterol elevation is present from birth because the variant is
    constitutional, but carriers are typically asymptomatic in childhood.
    GeneReviews therefore recommends lipid monitoring from age two years and
    permits statin therapy from around age eight.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Monitor lipid levels from age two years; consider noninvasive imaging modalities in adults; identify modifiable risk factors (e.g., smoking, sedentary behavior, hypertension, diabetes, obesity)."
    explanation: >-
      Establishes early-childhood lipid surveillance, which implies the
      biochemical phenotype precedes any clinical manifestation.
- phase: Cholesterol deposition and clinical presentation (young adulthood)
  notes: >-
    In the long-term British D374Y series, carriers presented about a decade
    earlier than severe LDLR-mutation heterozygotes, at a mean age of about 21
    years, with markedly higher pretreatment cholesterol.
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8+/-14.7 versus 30.2+/-15.7 years; P=0.003)"
    explanation: Quantifies the age at presentation in a PCSK9 gain-of-function cohort.
- phase: Premature atherosclerotic cardiovascular disease (adulthood)
  notes: >-
    Clinically manifest coronary artery disease occurred more than ten years
    earlier in the PCSK9 D374Y carriers than in severe LDLR-mutation
    heterozygotes.
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
    explanation: Quantifies the age at onset of premature coronary disease in this genotype.
pathophysiology:
- name: PCSK9 Gain-of-Function Variant
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  description: >-
    A heterozygous germline missense variant in PCSK9 that increases the
    protein's LDL-receptor-degrading activity. The classical alleles are S127R
    and F216L (the two variants of the founding French pedigrees) and D374Y
    (the severe British/Norwegian allele). The variants do not act through a
    common biochemical route: S127R and D374Y differ sharply in autocatalytic
    zymogen processing while F216L processes normally, and processing itself
    does not separate gain- from loss-of-function alleles. What they share is
    the functional output measured in cells - an excess of receptor-degrading
    PCSK9 activity.
  genetic_context:
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      The variant consequence is a gain of function: the mutant protein
      degrades more LDL receptor than wild-type PCSK9 does. This is recorded on
      the genetic context (the variant), not as a Descriptor modifier, because
      the claim is about the consequence of a specific allele.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:12730697
    reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis."
    explanation: >-
      Identifies the disease gene product as a liver-expressed subtilase acting
      in cholesterol homeostasis, the substrate of this trigger node.
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."
    explanation: >-
      GeneReviews specifies that it is the gain-of-function direction of PCSK9
      variation that causes FH, supporting the functional_impact_category here.
  downstream:
  - target: Hepatic PCSK9 Synthesis and Secretion
    causal_link_type: DIRECT
    description: >-
      The variant allele is transcribed and translated in the hepatocyte and
      the mutant protein is secreted into plasma, where it acts on the LDL
      receptor. This step is separated out because it is the point at which
      siRNA therapy acts.
    hypothesis_groups:
    - ldlr_degradation_model
    evidence:
    - reference: PMID:17080197
      reference_title: "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that purified PCSK9 added to the medium of HepG2 cells reduces the number of cell-surface LDLRs in a dose- and time-dependent manner. This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia."
      explanation: >-
        Directly quantifies the gain-of-function allele's excess
        receptor-degrading activity relative to wild-type PCSK9.
  - target: Increased Hepatic Secretion of ApoB-Containing Lipoproteins
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - hepatocyte expression of the mutant PCSK9 protein
    description: >-
      An alternative, non-mutually-exclusive route by which the same variants
      may raise circulating LDL - increased secretion of nascent
      apoB100-containing lipoprotein from the hepatocyte.
    hypothesis_groups:
    - apob_secretion_model
    evidence:
    - reference: PMID:15772090
      reference_title: "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Expression of the proposed pathogenic variants, but not of WT, S386A or F216L PCSK9, increases secretion of apolipoprotein B100-containing lipoproteins from the cells by 2-4-fold probably by reducing the degradation of nascent protein"
      explanation: >-
        Reports the variant-dependent increase in apoB100 lipoprotein secretion
        that defines this alternative causal edge.
- name: Hepatic PCSK9 Synthesis and Secretion
  biological_scale: CELLULAR
  description: >-
    PCSK9 is synthesised in the hepatocyte and secreted into the circulation,
    where it acts on LDL receptors on the same and other cells. Secreted PCSK9
    is sufficient on its own to deplete hepatic LDL receptors, as parabiosis
    between PCSK9-transgenic and wild-type mice shows. This node is the shared
    upstream of both the canonical receptor-degradation route and the
    alternative apoB-secretion route, and it is where hepatic PCSK9 knockdown
    acts.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:17080197
    reference_title: "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "After parabiosis, secreted PCSK9 was transferred to the circulation of wild-type mice and reduced the number of hepatic LDLRs to nearly undetectable levels."
    explanation: >-
      Shows that PCSK9 secreted by the liver acts through the circulation to
      deplete hepatic LDL receptors, establishing secretion as a distinct and
      necessary step.
  - reference: PMID:12730697
    reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis."
    explanation: Establishes the liver as the site of PCSK9 expression.
  downstream:
  - target: PCSK9 Binding to the LDL Receptor EGF-A Domain
    causal_link_type: DIRECT
    description: >-
      Circulating PCSK9 engages the LDL receptor at the hepatocyte surface;
      with a gain-of-function allele that engagement destroys more receptor.
    hypothesis_groups:
    - ldlr_degradation_model
    evidence:
    - reference: PMID:17080197
      reference_title: "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that purified PCSK9 added to the medium of HepG2 cells reduces the number of cell-surface LDLRs in a dose- and time-dependent manner. This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia."
      explanation: >-
        Quantifies the excess receptor-degrading activity of the D374Y
        gain-of-function allele acting from outside the cell.
- name: PCSK9 Binding to the LDL Receptor EGF-A Domain
  biological_scale: MOLECULAR
  description: >-
    Secreted PCSK9 binds the first epidermal growth factor-like repeat (EGF-A)
    of the LDL receptor's EGF homology domain at the hepatocyte surface. The
    interaction is calcium-dependent and its affinity rises steeply as pH falls
    from 7 to 5.2, so the complex tightens rather than dissociates as the
    receptor traverses the endosome. The evidence curated on this node is from
    wild-type recombinant PCSK9 and establishes where and how PCSK9 engages the
    receptor; the variant-specific excess is curated one node downstream, where
    it was measured as receptor loss rather than as binding affinity.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR."
    explanation: Localises the PCSK9 binding site on the LDL receptor to the EGF-A repeat.
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Binding to EGF-A was calcium-dependent and increased dramatically with reduction in pH from 7 to 5.2."
    explanation: >-
      Establishes the pH dependence that makes the complex persist through
      endocytosis rather than dissociating in the endosome.
  downstream:
  - target: Lysosomal Rerouting and Degradation of the Hepatocyte LDL Receptor
    causal_link_type: DIRECT
    description: >-
      Bound PCSK9 blocks the acid-dependent conformational change that would
      normally release the ligand and return the receptor to the surface.
    hypothesis_groups:
    - ldlr_degradation_model
    evidence:
    - reference: PMID:17452316
      reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling."
      explanation: States the mechanistic link between EGF-A binding and failure of receptor recycling.
- name: Lysosomal Rerouting and Degradation of the Hepatocyte LDL Receptor
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    The rate-limiting step of ADH3. Instead of recycling to the plasma
    membrane, the PCSK9-bound LDL receptor is diverted from the endosome to the
    lysosome and degraded. The hepatocyte surface receptor pool therefore falls
    even though the LDLR gene and protein are structurally normal. This is the
    node that distinguishes ADH3 from LDLR- and APOB-related FH, and it is the
    node that PCSK9-directed drugs act upstream of.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: LDL receptor recycling to the plasma membrane
    term:
      id: GO:0001881
      label: receptor recycling
    modifier: DECREASED
  - preferred_term: LDL receptor degradation
    term:
      id: GO:0032802
      label: low-density lipoprotein particle receptor catabolic process
    modifier: INCREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The addition of PCSK9, but not heat-inactivated PCSK9, to the medium of cultured hepatocytes resulted in redistribution of the receptor from the plasma membrane to lysosomes."
    explanation: Demonstrates the plasma-membrane-to-lysosome rerouting that defines this node.
  - reference: PMID:16571601
    reference_title: "Effect of mutations in the PCSK9 gene on the cell surface LDL receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."
    explanation: >-
      Quantifies the fall in hepatocyte surface LDL receptor caused specifically
      by the S127R and D374Y gain-of-function alleles.
  - reference: PMID:15358785
    reference_title: "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients."
    explanation: >-
      Shows the surface-receptor deficit in cells taken from S127R patients,
      not only in transfection models. The measurement is in lymphoblasts
      rather than hepatocytes, so it evidences the receptor-loss mechanism
      rather than the hepatic cell-type binding of this node.
  downstream:
  - target: Reduced Hepatic Clearance of Circulating LDL Particles
    causal_link_type: DIRECT
    description: >-
      Fewer hepatocyte surface receptors directly reduce receptor-mediated
      uptake of LDL from plasma.
    hypothesis_groups:
    - ldlr_degradation_model
    evidence:
    - reference: PMID:16571601
      reference_title: "Effect of mutations in the PCSK9 gene on the cell surface LDL receptors."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The two gain-of-function mutations had a 23% decreased level of cell surface LDLR and a 38% decreased level of internalization of LDL as compared with WT-PCSK9."
      explanation: Couples the surface-receptor deficit to a measured fall in LDL internalisation.
- name: Reduced Hepatic Clearance of Circulating LDL Particles
  biological_scale: TISSUE
  description: >-
    The liver is the principal route by which LDL leaves the circulation. With
    the hepatocyte receptor pool depleted, receptor-mediated uptake of LDL falls
    and the plasma residence time of LDL particles lengthens.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: receptor-mediated endocytosis of LDL
    term:
      id: GO:0006898
      label: receptor-mediated endocytosis
    modifier: DECREASED
  - preferred_term: low-density lipoprotein particle clearance
    term:
      id: GO:0034383
      label: low-density lipoprotein particle clearance
    modifier: DECREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of hepatic low density lipoprotein receptors (LDLR), the major route of clearance of circulating cholesterol."
    explanation: >-
      States that the hepatic LDL receptor is the major clearance route for
      circulating cholesterol, which is what this node reports as impaired.
  - reference: PMID:17080197
    reference_title: "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transgenic mice overexpressing human PCSK9 in liver secreted large amounts of the protein into plasma, which increased plasma LDL cholesterol concentrations to levels similar to those of LDLR-knockout mice."
    explanation: >-
      In vivo demonstration that excess secreted PCSK9 phenocopies loss of the
      LDL receptor at the level of plasma LDL cholesterol.
  downstream:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    causal_link_type: DIRECT
    description: Impaired hepatic removal raises the steady-state plasma LDL concentration.
    hypothesis_groups:
    - ldlr_degradation_model
    evidence:
    - reference: PMID:19191301
      reference_title: "Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a decreased risk of CHD."
      explanation: >-
        States the causal route from reduced LDL receptor levels to
        hypercholesterolemia for the gain-of-function alleles.
- name: Increased Hepatic Secretion of ApoB-Containing Lipoproteins
  biological_scale: CELLULAR
  description: >-
    A curated alternative contribution, not the canonical route. In rat
    hepatoma cells stably expressing the FH-associated PCSK9 variants, secretion
    of apoB100-containing lipoprotein rose 2-4 fold while LDL receptor content
    fell only slightly - the opposite emphasis to the hepatocyte
    receptor-degradation studies. Whether this contributes materially to the
    human phenotype, and in which cell context, is unresolved; the node is
    curated so the competing model is visible rather than lost in prose.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:15772090
    reference_title: "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This suggests that the variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers."
    explanation: >-
      The authors' own statement of the alternative mechanism this node
      represents.
  downstream:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    causal_link_type: DIRECT
    description: >-
      Increased output of apoB100 lipoprotein from the liver would raise
      circulating LDL independently of receptor number.
    hypothesis_groups:
    - apob_secretion_model
    evidence:
    - reference: PMID:15772090
      reference_title: "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This suggests that the variants of PCSK9 found in FH influence the secretion of apoB-containing lipoproteins, providing an explanation for the marked increase in circulating LDL in heterozygous carriers."
      explanation: Attributes the rise in circulating LDL to the secretion effect.
- name: Chronic Elevation of Plasma LDL Cholesterol
  biological_scale: ORGANISM
  description: >-
    Lifelong elevation of plasma LDL cholesterol from birth. In the best
    characterised PCSK9 cohort - 13 D374Y carriers from four unrelated British
    families - pretreatment total cholesterol averaged 13.6 mmol/L, materially
    higher than in severe LDLR-mutation heterozygotes, and remained higher on
    statin therapy.
  biological_processes:
  - preferred_term: cholesterol homeostasis
    term:
      id: GO:0042632
      label: cholesterol homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8+/-14.7 versus 30.2+/-15.7 years; P=0.003), had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004)"
    explanation: >-
      Quantifies the severity of the cholesterol elevation in PCSK9 D374Y
      carriers against LDLR-mutation comparators.
  downstream:
  - target: Hypercholesterolemia
    causal_link_type: DIRECT
    description: The node is the mechanistic substrate of the measured phenotype.
    evidence:
    - reference: PMID:16224054
      reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."
      explanation: Links the mechanism node to the observed clinical hypercholesterolemia.
  - target: Elevated LDL Cholesterol
    causal_link_type: DIRECT
    description: The LDL-C measurement is the direct readout of this node.
    evidence:
    - reference: PMID:19191301
      reference_title: "Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a decreased risk of CHD."
      explanation: States that the gain-of-function alleles act by raising LDL cholesterol.
  - target: Tendon Xanthomas
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic tissue retention of cholesterol-rich lipoproteins
    description: Prolonged cholesterol excess deposits in tendon tissue.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."
      explanation: >-
        GeneReviews attributes tendon xanthomas to extremely high cholesterol
        levels, the content of this node.
  - target: Xanthelasma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic tissue retention of cholesterol-rich lipoproteins
    description: The same chronic cholesterol excess deposits in periocular skin.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."
      explanation: GeneReviews names xanthelasma as an FH cholesterol-deposition sign.
  - target: Corneal Arcus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic tissue retention of cholesterol-rich lipoproteins
    description: The same chronic cholesterol excess deposits at the corneal margin.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."
      explanation: >-
        GeneReviews attributes corneal arcus to cholesterol deposition, the
        content of this node.
  - target: Subendothelial Retention of ApoB-Containing Lipoproteins
    causal_link_type: DIRECT
    description: >-
      Sustained excess of circulating apoB lipoprotein drives its infiltration
      and retention in the arterial intima.
    evidence:
    - reference: PMID:26844337
      reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis."
      explanation: >-
        Links the circulating apoB burden to arterial-wall retention as the
        initiating event of atherogenesis. Evidence source is OTHER because this
        is a review chapter.
- name: Subendothelial Retention of ApoB-Containing Lipoproteins
  conforms_to: "atherogenesis#Endothelial Dysfunction and Subendothelial LDL Retention"
  biological_scale: TISSUE
  description: >-
    The ADH3 substitution at the atherogenesis module's retention trigger: the
    disease-specific driver is the PCSK9-driven LDL/apoB burden, but the
    initiating event - infiltration and retention of apoB-containing
    lipoproteins in the arterial intima, followed by their oxidative
    modification and an inflammatory response - is the conserved one.
  cell_types:
  - preferred_term: vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: cholesterol homeostasis in the arterial wall
    term:
      id: GO:0042632
      label: cholesterol homeostasis
    modifier: DYSREGULATED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: tunica intima
    term:
      id: UBERON:0002523
      label: tunica intima
  evidence:
  - reference: PMID:26844337
    reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Arterial injury causes endothelial dysfunction promoting modification of apoB containing lipoproteins and infiltration of monocytes into the subendothelial space."
    explanation: >-
      Describes endothelial dysfunction with modification of retained apoB
      lipoprotein and monocyte entry, the content of this module node. Evidence
      source is OTHER because this is a review chapter.
  downstream:
  - target: Macrophage Foam Cell Formation
    causal_link_type: DIRECT
    description: >-
      Retained, modified apoB lipoprotein is internalised by intimal
      macrophages.
    evidence:
    - reference: PMID:26844337
      reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis."
      explanation: >-
        States the retained-lipoprotein-to-foam-cell step. Evidence source is
        OTHER because this is a review chapter.
- name: Macrophage Foam Cell Formation
  conforms_to: "atherogenesis#Monocyte Recruitment and Macrophage Foam Cell Formation"
  biological_scale: CELLULAR
  description: >-
    Monocytes recruited into the intima differentiate into macrophages and
    internalise the modified apoB lipoproteins, becoming lipid-laden foam
    cells - the hallmark of the fatty streak. Macrophage inflammation then
    feeds back on lipoprotein oxidation, endothelial activation and further
    monocyte recruitment.
  cell_types:
  - preferred_term: foam cell (lipid-laden macrophage)
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: foam cell differentiation
    term:
      id: GO:0090077
      label: foam cell differentiation
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: tunica intima
    term:
      id: UBERON:0002523
      label: tunica intima
  evidence:
  - reference: PMID:26844337
    reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Macrophage inflammation results in enhanced oxidative stress and cytokine/chemokine secretion, causing more LDL/remnant oxidation, endothelial cell activation, monocyte recruitment, and foam cell formation."
    explanation: >-
      Documents the feed-forward inflammatory amplification of foam-cell
      formation. Evidence source is OTHER because this is a review chapter.
  downstream:
  - target: Smooth Muscle Cell Switching and Fibrofatty Plaque Formation
    causal_link_type: DIRECT
    description: >-
      Macrophage-derived chemoattractants recruit smooth muscle cells that build
      the plaque's matrix.
    evidence:
    - reference: PMID:26844337
      reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells."
      explanation: >-
        States the foam-cell-to-smooth-muscle-cell step. Evidence source is
        OTHER because this is a review chapter.
- name: Smooth Muscle Cell Switching and Fibrofatty Plaque Formation
  conforms_to: "atherogenesis#Smooth Muscle Cell Switching and Fibrofatty Plaque Formation"
  biological_scale: TISSUE
  description: >-
    Vascular smooth muscle cells infiltrate the lipid-rich intima, proliferate
    and secrete extracellular matrix, converting the fatty streak into an
    organised fibrofatty plaque with a matrix-rich fibrous cap. This is the
    conserved central effector of the atherogenesis module. The ADH3-specific
    claim curated here is only that carriers reach clinically manifest coronary
    atherosclerosis earlier than severe LDLR-mutation heterozygotes; the
    lesion-level steps are the module's conserved ones and are evidenced from
    general atherosclerosis sources.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle cell proliferation
    term:
      id: GO:0048661
      label: positive regulation of smooth muscle cell proliferation
    modifier: INCREASED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: artery
    term:
      id: UBERON:0001637
      label: artery
  evidence:
  - reference: PMID:26844337
    reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets."
    explanation: >-
      Establishes smooth-muscle-cell matrix production as the plaque-building
      step. Evidence source is OTHER because this is a review chapter.
  - reference: PMID:37595697
    reference_title: "The microenvironment of the atheroma expresses phenotypes of plaque instability."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "vascular smooth muscle cell phenotypic switching through transdifferentiation and stem/progenitor cell activation resulting in the promotion of inflammation, calcification, and secretion of extracellular matrix, altering fibrous cap structure, and necrotic core growth."
    explanation: >-
      Describes the smooth-muscle phenotypic switch and matrix secretion that
      the module node names. Evidence source is OTHER because this is a
      histopathology review.
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
    explanation: >-
      Human evidence that PCSK9 gain-of-function carriers reach clinically
      manifest coronary atherosclerosis earlier than severe LDLR-mutation
      heterozygotes, licensing this atherogenesis branch for ADH3.
  downstream:
  - target: Advanced Atheroma with Necrotic Core and Fibrous Cap
    causal_link_type: DIRECT
    description: >-
      Continued lipid accumulation and unresolved inflammation convert the
      fibrofatty plaque into an advanced, vulnerable atheroma.
    evidence:
    - reference: PMID:26844337
      reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Unresolved inflammation results in formation of vulnerable plaques characterized by enhanced macrophage apoptosis and defective efferocytosis of apoptotic cells resulting in necrotic cell death"
      explanation: >-
        States the progression from plaque to vulnerable, necrotic-core lesion.
        Evidence source is OTHER because this is a review chapter.
  - target: Peripheral Arterial Disease
    causal_link_type: DIRECT
    description: >-
      The same lumen-narrowing fibrofatty lesion occurring in the limb arteries
      produces flow-limiting peripheral disease. Attached here rather than to
      the plaque-rupture node because peripheral arterial disease in this
      context is chronic stenosis, not an acute thrombotic event - which is why
      it branches off the stenotic stage in parallel with, not downstream of,
      the coronary events.
    evidence:
    - reference: PMID:30085243
      reference_title: "Familial Hypercholesterolemia and Risk of Peripheral Arterial Disease and Chronic Kidney Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Compared with individuals with unlikely FH, multivariable adjusted ORs (95% CIs) of PAD were 1.84 (1.70 to 2.00) in those with possible FH and 1.36 (1.00 to 1.84) in individuals with probable/definite FH."
      explanation: >-
        Establishes that the FH atherogenic state modeled by this branch raises
        peripheral arterial disease risk. The cohort is clinically defined FH,
        not PCSK9-genotyped, so this licenses the edge at the FH level rather
        than evidencing an ADH3-specific magnitude.
- name: Advanced Atheroma with Necrotic Core and Fibrous Cap
  conforms_to: "atherogenesis#Advanced Atheroma with Necrotic Core and Fibrous Cap"
  biological_scale: TISSUE
  description: >-
    Macrophage apoptosis and defective efferocytosis enlarge a necrotic lipid
    core, while matrix loss and collagen degradation thin the overlying fibrous
    cap, converting a stable plaque into a vulnerable one. Curated as the
    conserved module stage; no ADH3-specific plaque-histology series is cited.
  cell_types:
  - preferred_term: foam cell (lipid-laden macrophage)
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: DECREASED
  locations:
  - preferred_term: artery
    term:
      id: UBERON:0001637
      label: artery
  evidence:
  - reference: PMID:26844337
    reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "leading to increased smooth muscle cell death, decreased extracellular matrix production, and collagen degradation by macrophage proteases."
    explanation: >-
      Describes the matrix loss and cap thinning that define the advanced,
      vulnerable atheroma. Evidence source is OTHER because this is a review
      chapter.
  downstream:
  - target: Plaque Rupture, Thrombosis, and Ischemic Events
    causal_link_type: DIRECT
    description: A thinned fibrous cap can rupture and expose thrombogenic material.
    evidence:
    - reference: PMID:26844337
      reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE."
      explanation: >-
        States the rupture-to-ischemic-event step. Evidence source is OTHER
        because this is a review chapter.
- name: Plaque Rupture, Thrombosis, and Ischemic Events
  conforms_to: "atherogenesis#Plaque Rupture, Thrombosis, and Ischemic Events"
  biological_scale: ORGANISM
  description: >-
    Cap rupture exposes thrombogenic plaque material, luminal thrombosis
    follows, and the resulting coronary occlusion produces the clinical
    ischemic events - angina and myocardial infarction - that occur more than a
    decade earlier in PCSK9 gain-of-function carriers than in severe
    LDLR-mutation heterozygotes.
  locations:
  - preferred_term: artery
    term:
      id: UBERON:0001637
      label: artery
  evidence:
  - reference: PMID:26844337
    reference_title: "The Role of Lipids and Lipoproteins in Atherosclerosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE."
    explanation: >-
      States the conserved rupture-thrombosis-ischemia step. Evidence source is
      OTHER because this is a review chapter.
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
    explanation: >-
      ADH3-specific evidence for the earlier timing of clinically manifest
      coronary disease at this node.
  downstream:
  - target: Premature Coronary Artery Disease
    causal_link_type: DIRECT
    description: The arterial lesion burden manifests clinically as premature coronary disease.
    evidence:
    - reference: PMID:16224054
      reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
      explanation: Directly links the atherosclerotic branch to the premature-CAD phenotype.
  - target: Myocardial Infarction
    causal_link_type: DIRECT
    description: Acute coronary occlusion produces myocardial infarction.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
      explanation: >-
        GeneReviews states the plaque-to-event link for FH, of which
        PCSK9-related FH is one molecular form.
  - target: Angina Pectoris
    causal_link_type: DIRECT
    description: Flow-limiting coronary lesions produce exertional angina.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
      explanation: GeneReviews lists angina among the plaque-driven events of FH.
mechanistic_hypotheses:
- hypothesis_group_id: ldlr_degradation_model
  hypothesis_label: PCSK9-accelerated LDL receptor degradation
  status: CANONICAL
  description: >-
    The accepted model: gain-of-function PCSK9 binds the hepatocyte LDL
    receptor's EGF-A domain, reroutes it to the lysosome, depletes the surface
    receptor pool, and so reduces hepatic LDL clearance. This model is what
    PCSK9-directed therapeutics were designed against and what their LDL-C
    lowering confirms in vivo.
  evidence:
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded."
    explanation: The core mechanistic claim of the canonical model.
- hypothesis_group_id: apob_secretion_model
  hypothesis_label: Increased hepatic apoB-lipoprotein secretion
  status: ALTERNATIVE
  description: >-
    A competing/superimposed model in which FH-associated PCSK9 variants raise
    circulating LDL chiefly by increasing secretion of nascent
    apoB100-containing lipoprotein from the hepatocyte, rather than by
    depleting the LDL receptor. In the study that proposed it, receptor content
    was only slightly reduced by D374Y and S127R while apoB secretion rose 2-4
    fold. The two models are not mutually exclusive, and the alternative has
    not displaced the receptor-degradation model as the therapeutic rationale.
  evidence:
  - reference: PMID:15772090
    reference_title: "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "no differences in LDL-receptor content were observed in cells expressing WT, S386A or F216L PCSK9 and only a small reduction in cells expressing the D374Y or S127R mutants."
    explanation: >-
      The observation that motivates the alternative model - a small receptor
      effect alongside a large secretion effect in this system.
discussions:
- discussion_id: adh3_receptor_degradation_vs_apob_secretion
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    In human PCSK9 gain-of-function carriers, how much of the LDL-cholesterol
    elevation is attributable to accelerated LDL receptor degradation versus
    increased hepatic secretion of apoB100-containing lipoprotein?
  attaches_to:
  - "pathophysiology#Increased Hepatic Secretion of ApoB-Containing Lipoproteins"
  - "pathophysiology#Chronic Elevation of Plasma LDL Cholesterol"
  rationale: >-
    Two in vitro systems give opposite emphases for the same PCSK9 variants.
    Hepatocyte and HepG2 studies show a large fall in cell-surface LDL receptor
    with D374Y and S127R; McArdle-7777 rat hepatoma cells expressing the same
    variants show only a small receptor reduction but a 2-4 fold rise in
    apoB100-lipoprotein secretion. No human in vivo measurement apportions the
    LDL-C elevation between the two routes. This matters therapeutically: a
    secretion-dominant contribution would not be neutralised by extracellular
    PCSK9 blockade, whereas hepatic PCSK9 knockdown would address both.
  evidence:
  - reference: PMID:15772090
    reference_title: "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "no differences in LDL-receptor content were observed in cells expressing WT, S386A or F216L PCSK9 and only a small reduction in cells expressing the D374Y or S127R mutants."
    explanation: >-
      Documents the discrepant receptor result that motivates this gap.
  proposed_experiments:
  - experiment_id: adh3_ldl_apob_kinetics
    name: Stable-isotope LDL apoB kinetics in PCSK9 gain-of-function carriers
    description: >-
      Measure LDL apoB100 production rate and fractional catabolic rate by
      stable-isotope turnover in genotyped PCSK9 gain-of-function heterozygotes
      versus LDLR-mutation heterozygotes and normolipidemic controls, to
      partition the LDL-C elevation between overproduction and impaired
      clearance.
  - experiment_id: adh3_mab_vs_sirna_response
    name: Head-to-head response to extracellular versus intracellular PCSK9 blockade
    description: >-
      Compare LDL-C and apoB kinetic response to a PCSK9 monoclonal antibody
      (extracellular neutralisation) versus inclisiran (hepatic synthesis
      knockdown) within the same PCSK9 gain-of-function carriers; a
      secretion-dominant mechanism predicts a differential response.
phenotypes:
- category: Biochemical
  name: Hypercholesterolemia
  description: >-
    Lifelong elevation of total and LDL cholesterol, present from birth and
    typically more severe than in LDLR-mutation heterozygotes for the D374Y
    allele.
  phenotype_term:
    preferred_term: Hypercholesterolemia
    term:
      id: HP:0003124
      label: Hypercholesterolemia
    temporality: CHRONIC
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."
    explanation: >-
      Documents severe hypercholesterolemia as the defining clinical phenotype
      of PCSK9 D374Y carriers.
  - reference: PMID:19191301
    reference_title: "Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Several PCSK9 variants have been identified, some of them are gain-of-function mutations causing hypercholesterolemia by a reduction of low-density lipoprotein (LDL) receptor levels; while others are loss-of-function variants associated with a reduction of LDL-cholesterol (LDL-C) levels and a decreased risk of CHD."
    explanation: Attributes hypercholesterolemia to the gain-of-function PCSK9 alleles.
- category: Biochemical
  name: Elevated LDL Cholesterol
  description: >-
    Elevated plasma LDL cholesterol concentration is the measured abnormality
    used both for diagnosis and for monitoring treatment response.
  phenotype_term:
    preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
    temporality: CHRONIC
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A clinical diagnosis of FH can be established in a proband with characteristic clinical features and significantly elevated LDL-C levels (typically >190 mg/dL in adults and >160 mg/dL in children)."
    explanation: >-
      GeneReviews sets the elevated-LDL-C threshold that defines the biochemical
      phenotype in PCSK9-related FH as in the other FH genes.
- category: Cardiovascular
  name: Premature Coronary Artery Disease
  description: >-
    Accelerated coronary atherosclerosis presenting substantially earlier than
    in severe LDLR-mutation heterozygotes - by more than a decade in the
    British D374Y cohort.
  phenotype_term:
    preferred_term: Coronary artery atherosclerosis
    term:
      id: HP:0001677
      label: Coronary artery atherosclerosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002)"
    explanation: >-
      Quantifies the earlier onset of premature coronary artery disease in
      PCSK9 D374Y carriers relative to LDLR-mutation heterozygotes.
  - reference: PMID:17452316
    reference_title: "Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Gain-of-function mutations in PCSK9 cause hypercholesterolemia and premature atherosclerosis, whereas loss-of-function mutations result in hypocholesterolemia and protection from heart disease."
    explanation: >-
      Background statement of the established PCSK9 genotype-phenotype
      relationship, cited only as a secondary corroboration of the
      PCSK9-carrier cohort finding above. Evidence source is OTHER because the
      sentence is the paper's framing of prior human genetics, not a result of
      this in vitro study.
- category: Cardiovascular
  name: Myocardial Infarction
  description: >-
    Myocardial infarction is the archetypal premature cardiovascular event of
    familial hypercholesterolemia, including its PCSK9-related form.
  phenotype_term:
    preferred_term: Myocardial infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
    explanation: >-
      GeneReviews lists myocardial infarction among the premature cardiovascular
      events of FH, of which PCSK9-related FH is one molecular form.
- category: Cardiovascular
  name: Angina Pectoris
  description: Exertional angina as a manifestation of premature coronary atherosclerosis.
  phenotype_term:
    preferred_term: Angina pectoris
    term:
      id: HP:0001681
      label: Angina pectoris
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely."
    explanation: GeneReviews lists angina among the premature cardiovascular events of FH.
- category: Cardiovascular
  name: Peripheral Arterial Disease
  description: >-
    Atherosclerotic narrowing of the limb arteries. Less prominent than the
    coronary disease that dominates the FH phenotype, but measurably more
    frequent than in the general population, and a low ankle-brachial index
    identifies FH patients at very high myocardial-infarction risk.
  phenotype_term:
    preferred_term: Peripheral arterial disease
    term:
      id: HP:0004950
      label: Peripheral arterial stenosis
  evidence:
  - reference: PMID:30085243
    reference_title: "Familial Hypercholesterolemia and Risk of Peripheral Arterial Disease and Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with individuals with unlikely FH, multivariable adjusted ORs (95% CIs) of PAD were 1.84 (1.70 to 2.00) in those with possible FH and 1.36 (1.00 to 1.84) in individuals with probable/definite FH."
    explanation: >-
      Quantifies elevated peripheral arterial disease risk in a general-population
      FH cohort of 106,172 individuals.
  notes: >-
    Evidence is from clinically defined FH, not a PCSK9-genotyped cohort. Kept
    without a `frequency:` band because no PCSK9-specific frequency is
    available and the FH-wide odds ratios do not translate into one.
- category: Dermatologic
  name: Tendon Xanthomas
  description: >-
    Cholesterol deposits in tendons, classically the Achilles tendon and the
    extensor tendons of the hands, worsening with age.
  phenotype_term:
    preferred_term: Tendon xanthomatosis
    term:
      id: HP:0010874
      label: Tendon xanthomatosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels."
    explanation: GeneReviews describes tendon xanthomas as an FH cholesterol-deposition sign.
- category: Dermatologic
  name: Xanthelasma
  description: Yellowish waxy cholesterol deposits around the eyelids.
  phenotype_term:
    preferred_term: Xanthelasma
    term:
      id: HP:0001114
      label: Xanthelasma
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids."
    explanation: GeneReviews describes xanthelasma as an FH cholesterol-deposition sign.
- category: Ophthalmologic
  name: Corneal Arcus
  description: >-
    Opaque ring at the corneal margin from cholesterol deposition, appearing at
    a younger age than in the general population.
  phenotype_term:
    preferred_term: Corneal arcus
    term:
      id: HP:0001084
      label: Corneal arcus
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH."
    explanation: GeneReviews describes early corneal arcus as an FH cholesterol-deposition sign.
biochemical:
- name: Plasma LDL Cholesterol
  notes: >-
    The primary biochemical marker of ADH3, used for diagnosis, cascade
    screening of relatives, and monitoring of lipid-lowering therapy.
  biomarker_term:
    preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1+/-3.0 versus 6.5+/-0.9 mmol/L; P=0.006)"
    explanation: >-
      Shows serum cholesterol used as the tracked biochemical readout before and
      during treatment in PCSK9 D374Y carriers.
- name: Plasma Lipoprotein(a)
  notes: >-
    A second, independent lipid measurement recommended at least once in anyone
    with FH. It matters here for two reasons that pull in opposite directions.
    As a *confounder*, lipoprotein(a) cholesterol is counted inside a
    conventionally measured LDL-C and can therefore inflate a clinical FH score
    in someone who carries no FH mutation - which is one reason molecular
    testing, not the lipid panel, is what establishes ADH3. As a *modifier*, a
    high concentration multiplies myocardial-infarction risk on top of the FH
    phenotype and is one of the seven variables in the FH-Risk-Score. It is not
    part of the PCSK9 mechanism and is not altered by it.
  biomarker_term:
    preferred_term: Elevated circulating lipoprotein(a) concentration
    term:
      id: HP:6000521
      label: Elevated circulating lipoprotein(a) concentration
  evidence:
  - reference: PMID:27185354
    reference_title: "High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that all individuals with familial hypercholesterolaemia should have their lipoprotein(a) measured in order to identify those with the highest concentrations, and as a result, the highest risk of myocardial infarction."
    explanation: >-
      Establishes measurement of lipoprotein(a) as part of the FH workup and
      its role as a risk modifier.
  - reference: PMID:27185354
    reference_title: "High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High lipoprotein(a) cholesterol accounted for a quarter of all individuals diagnosed with clinical familial hypercholesterolaemia"
    explanation: >-
      Supports the confounder role noted above - lipoprotein(a) cholesterol
      inflates the clinically measured LDL-C used by the phenotypic criteria.
  - reference: PMID:34433300
    reference_title: "Familial Hypercholesterolemia-Risk-Score: A New Score Predicting Cardiovascular Events and Cardiovascular Mortality in Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75"
    explanation: >-
      Places lipoprotein(a) among the prognostic variables of a validated FH
      risk score.
genetic:
- name: PCSK9
  gene_term:
    preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    PCSK9 (proprotein convertase subtilisin/kexin type 9, 1p32) is the causal
    gene of ADH3. Heterozygous gain-of-function missense alleles increase
    PCSK9-mediated degradation of the hepatocyte LDL receptor. Reported
    disease-causing alleles include S127R and F216L (the founding French
    pedigrees) and D374Y (the severe British allele). Allele-level biochemistry
    is heterogeneous: S127R and D374Y differ sharply in autocatalytic zymogen
    processing and F216L processes normally, while D374Y is roughly tenfold
    more potent than wild-type PCSK9 at depleting cell-surface receptor.
    Zymogen processing does not itself discriminate gain- from loss-of-function
    alleles, so allele mechanism should not be generalised from one variant to
    another.

    Penetrance and expressivity: penetrance for the biochemical phenotype
    (LDL-C elevation) is high but age-dependent, and has not been quantified
    per allele; penetrance for clinical atherosclerotic disease is frankly
    incomplete, since it depends on the allele's effect size, treatment,
    lipoprotein(a), and conventional risk factors. No ADH3-specific penetrance
    estimate is curated here because none is available - stating the absence is
    more useful than borrowing an FH-wide figure.

    Mirror-image genetics: PCSK9 also carries loss-of-function alleles, which
    lower LDL-C and reduce coronary risk lifelong. These are recorded here only
    as reciprocal genetic support for this entry's central mechanism - a
    dose-response across the full range of PCSK9 activity - and as the rationale
    for PCSK9-directed therapy. They are not part of the ADH3 disease entity and
    no protective-allele phenotype is curated in this file.
  evidence:
  - reference: PMID:12730697
    reference_title: "Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH."
    explanation: Establishes PCSK9 as the causal gene at the HCHOLA3 locus.
  - reference: PMID:15358785
    reference_title: "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The S127R and D374Y mutations result in approximately 50-60% and > or =98% decrease in zymogen processing, respectively."
    explanation: >-
      Supports the allele-level heterogeneity noted above: S127R and D374Y
      differ markedly from each other in their effect on zymogen processing.
  - reference: PMID:16554528
    reference_title: "Sequence variations in PCSK9, low LDL, and protection against coronary heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD"
    explanation: >-
      The reciprocal, loss-of-function arm of the same gene: nonsense PCSK9
      alleles lower LDL-C and coronary risk lifelong. Cited as mirror-image
      support for the gain-of-function mechanism asserted in this entry, not as
      an ADH3 phenotype.
  variants:
  - name: PCSK9 p.Ser127Arg
    description: >-
      One of the two founding ADH3 alleles. Markedly impairs autocatalytic
      zymogen processing and reduces cell-surface LDL receptor in patient
      lymphoblasts.
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:15358785
      reference_title: "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients."
      explanation: Functional consequence of S127R measured in patient-derived cells.
  - name: PCSK9 p.Phe216Leu
    description: >-
      The second founding ADH3 allele, reported alongside S127R in the original
      French pedigrees. Zymogen processing is normal, so its gain of function is
      not explained by the processing defect seen with S127R.
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:15358785
      reference_title: "NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "F216L, and R218S natural mutants resulted in normal zymogen processing."
      explanation: Documents that F216L retains normal zymogen processing.
  - name: PCSK9 p.Asp374Tyr
    description: >-
      The severe ADH3 allele. Roughly tenfold more potent than wild-type PCSK9
      at reducing cell-surface LDL receptor, and associated with a clinical
      phenotype more severe than severe LDLR-mutation heterozygosity.
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:17080197
      reference_title: "Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This activity was approximately 10-fold greater for a gain-of-function mutant, PCSK9(D374Y), that causes hypercholesterolemia."
      explanation: Quantifies the increased receptor-degrading potency of D374Y.
    - reference: PMID:15772090
      reference_title: "Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We have identified the D374Y mutant of PCSK9 in three FH families of English origin; all 12 affected individuals have unusually severe hypercholesterolaemia and require more stringent treatment than typical FH patients, who are heterozygous for defects in the LDL receptor."
      explanation: Documents the severe clinical phenotype of D374Y carriers.
  - name: PCSK9 p.Arg496Trp
    description: >-
      A C-terminal cysteine-histidine-rich domain module 1 (CM1) gain-of-function
      allele. Mechanistically distinct from the three alleles above: rather than
      altering zymogen processing or receptor affinity directly, it abolishes
      binding of PCSK9 to LDL particles. Because LDL-bound PCSK9 is less able to
      degrade the receptor, losing that inhibitory association leaves more free,
      active PCSK9 - a third route to the same gain of function. Included as a
      representative of the C-terminal variant class rather than as a
      well-characterised ADH3 pedigree allele.
    gene:
      preferred_term: PCSK9
      term:
        id: hgnc:20001
        label: PCSK9
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:36187800
      reference_title: "Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We previously reported that an R496W GOF mutation in a region of PCSK9 known as cysteine-histidine-rich domain module 1 (CM1) prevents LDL binding in vitro"
      explanation: >-
        Identifies R496W as a CM1-domain gain-of-function allele acting through
        loss of LDL binding.
    - reference: PMID:36187800
      reference_title: "Pathogenic gain-of-function mutations in the prodomain and C-terminal domain of PCSK9 inhibit LDL binding."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Herein, we identify additional GOF mutations that inhibit LDL association, localized either within CM1 or a surface-exposed region in the PCSK9 prodomain."
      explanation: >-
        Establishes loss of LDL association as a shared mechanism spanning two
        distinct PCSK9 domains, which is what makes this a separate variant
        class from S127R/F216L/D374Y as classically described.
environmental:
- name: High Saturated and Trans Fat Intake
  description: >-
    Dietary saturated and trans fat raise circulating LDL on top of the
    PCSK9-driven clearance defect. This is the one modifiable exposure that
    acts on the lipid node itself rather than on the vascular outcome, which is
    why diet is additive to, and never a substitute for, pharmacotherapy in
    this genotype.
  exposure_term:
    preferred_term: high dietary saturated and trans fat exposure
    modifier: INCREASED
    term:
      id: ECTO:0090010
      label: exposure to lipid in food
  influences_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Dietary fat intake adds to the circulating LDL burden already produced by
      the inherited receptor-degradation defect.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."
      explanation: >-
        GeneReviews lists high saturated and trans fat intake among the
        exposures to avoid in FH, acting at the lipid level itself.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking."
    explanation: >-
      The corresponding dietary recommendation, establishing this as a
      modifiable exposure in FH management.
- name: Tobacco Smoking
  description: >-
    Smoking does not raise LDL cholesterol, so it acts on the vascular arm
    rather than on any lipid node. Against a lifetime LDL burden that begins at
    birth, cessation is disproportionately valuable.
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  influences_mechanisms:
  - target: Subendothelial Retention of ApoB-Containing Lipoproteins
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Smoking aggravates endothelial dysfunction, the permissive condition for
      subendothelial lipoprotein retention, without altering the LDL burden.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."
      explanation: GeneReviews lists smoking first among the exposures to avoid in FH.
  evidence:
  - reference: PMID:34433300
    reference_title: "Familial Hypercholesterolemia-Risk-Score: A New Score Predicting Cardiovascular Events and Cardiovascular Mortality in Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FH-Risk-Score incorporates 7 clinical variables: sex, age, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, hypertension, smoking, and lipoprotein (a) (Lp(a)) with a Harrell C-index for 10-year ASCVD event of 0.75"
    explanation: >-
      Smoking is retained as one of only seven predictors in a 10-year ASCVD
      risk score derived prospectively in 3881 heterozygous FH patients. That
      is the quantitative basis for curating smoking as a modifiable exposure
      acting on the vascular arm rather than on the lipid node.
- name: Sedentary Lifestyle
  description: >-
    Physical inactivity, with the obesity, hypertension and diabetes that
    accompany it, adds conventional atherosclerotic risk on top of the
    inherited lipid lesion.
  exposure_term:
    preferred_term: exposure to sedentary lifestyle
    term:
      id: ECTO:6000004
      label: exposure to sedentary lifestyle
  influences_mechanisms:
  - target: Subendothelial Retention of ApoB-Containing Lipoproteins
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Acts on the vascular arm through the conventional risk factors it
      promotes, not on the PCSK9-LDL receptor axis.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."
      explanation: GeneReviews lists sedentary lifestyle among the exposures to avoid in FH.
  evidence:
  - reference: PMID:35294538
    reference_title: "Association of the Interaction Between Familial Hypercholesterolemia Variants and Adherence to a Healthy Lifestyle With Risk of Coronary Artery Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among carriers, a favorable lifestyle conferred 86% lower risk of CAD compared with an unfavorable lifestyle (hazard ratio, 0.14 [95% CI, 0.04-0.41])."
    explanation: >-
      In UK Biobank carriers of a monogenic FH variant, a four-component
      lifestyle score whose components include regular exercise stratified
      coronary risk steeply. This quantifies physical inactivity as a
      modifiable exposure in monogenic FH specifically, not only in the general
      population.
treatments:
- name: Evolocumab
  description: >-
    Fully human monoclonal antibody that binds circulating PCSK9 and prevents
    it from engaging the hepatocyte LDL receptor, restoring receptor recycling
    and hepatic LDL clearance. In heterozygous familial hypercholesterolemia it
    lowers LDL cholesterol by approximately 60% on top of statin therapy, and in
    established atherosclerotic cardiovascular disease it reduces cardiovascular
    events. It is the mechanistically direct therapy for ADH3: the drug target
    is the mutated protein itself.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: evolocumab
      term:
        id: NCIT:C174672
        label: Evolocumab
  target_mechanisms:
  - target: PCSK9 Binding to the LDL Receptor EGF-A Domain
    treatment_effect: INHIBITS
    description: >-
      Antibody neutralisation of circulating PCSK9 blocks the EGF-A engagement
      that initiates receptor degradation.
    evidence:
    - reference: PMID:28304224
      reference_title: "Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%."
      explanation: >-
        States the drug's target and its effect on the LDL cholesterol output
        of this pathway. This is the trial's background statement of the
        established drug mechanism, cited for the drug-target identity; the
        trial's own outcome result is cited separately on the treatment.
  evidence:
  - reference: PMID:25282519
    reference_title: "PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo."
    explanation: >-
      Randomised evidence of efficacy in heterozygous familial
      hypercholesterolemia, the clinical setting of ADH3.
  - reference: PMID:28304224
    reference_title: "Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events."
    explanation: >-
      Outcome evidence that PCSK9 inhibition reduces cardiovascular events, the
      clinical endpoint this disease threatens.
  notes: >-
    The cardiovascular-outcome evidence (FOURIER) was generated in patients with
    established atherosclerotic cardiovascular disease, not in a
    PCSK9-genotyped ADH3 cohort. No trial has been powered on PCSK9
    gain-of-function carriers specifically.
- name: Alirocumab
  description: >-
    Human monoclonal antibody against PCSK9, the same mechanism as evolocumab.
    In patients with recent acute coronary syndrome on high-intensity statin it
    reduced recurrent ischemic cardiovascular events.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alirocumab
      term:
        id: NCIT:C174849
        label: Alirocumab
  target_mechanisms:
  - target: PCSK9 Binding to the LDL Receptor EGF-A Domain
    treatment_effect: INHIBITS
    description: >-
      Antibody binding to circulating PCSK9 prevents the receptor engagement
      step.
    evidence:
    - reference: PMID:30403574
      reference_title: "Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy."
      explanation: >-
        Identifies alirocumab's molecular target as PCSK9. This is the trial's
        aim sentence rather than a result; it is cited for the drug-target
        identity only, with the trial's outcome result cited separately on the
        treatment itself.
  evidence:
  - reference: PMID:30403574
    reference_title: "Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo."
    explanation: Randomised outcome evidence for PCSK9 antibody therapy.
  notes: >-
    As for evolocumab, the outcome trial enrolled post-acute-coronary-syndrome
    patients rather than genotyped PCSK9 gain-of-function carriers.
- name: Inclisiran
  description: >-
    A small interfering RNA that silences PCSK9 messenger RNA in the
    hepatocyte, suppressing synthesis of the protein rather than neutralising
    it after secretion. Given twice yearly after loading. In heterozygous
    familial hypercholesterolemia it lowered LDL cholesterol by roughly 40%
    versus baseline (about 48 percentage points versus placebo), with
    reductions reported across FH genotypes.
  therapeutic_modality: SIRNA
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: inclisiran
      term:
        id: NCIT:C170062
        label: Inclisiran
  target_mechanisms:
  - target: Hepatic PCSK9 Synthesis and Secretion
    treatment_effect: INHIBITS
    description: >-
      Hepatic silencing of PCSK9 messenger RNA reduces production of the mutant
      protein itself, acting upstream of its secretion and receptor engagement.
      This is the one PCSK9-directed mechanism that would also blunt an
      intracellular (apoB-secretion) contribution.
    evidence:
    - reference: PMID:32197277
      reference_title: "Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia."
      explanation: >-
        States inclisiran's mechanism as inhibition of hepatic PCSK9 synthesis.
        The sentence reports the earlier phase 2 result rather than this
        trial's own finding, and is cited for the mechanism only; ORION-9's own
        LDL-C result is cited separately on the treatment.
  evidence:
  - reference: PMID:32197277
    reference_title: "Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile."
    explanation: Randomised evidence of efficacy in heterozygous familial hypercholesterolemia.
  - reference: PMID:32197277
    reference_title: "Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia."
    explanation: >-
      Reports that the LDL-lowering effect was seen across FH genotypes, the
      closest available evidence that it applies to PCSK9-gene carriers.
  notes: >-
    ORION-9 reported LDL cholesterol, not cardiovascular events; no
    outcome trial of inclisiran was available for citation here. The
    genotype statement is an all-genotype subgroup observation, not a
    PCSK9-carrier-specific result.
- name: Statin Therapy
  description: >-
    HMG-CoA reductase inhibition is first-line lipid-lowering therapy in
    familial hypercholesterolemia and is the background on which PCSK9-directed
    agents are added. PCSK9 D374Y carriers respond to statins but remain at
    substantially higher cholesterol on treatment than LDLR-mutation
    heterozygotes, which is why they usually need combination therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atorvastatin
      term:
        id: CHEBI:39548
        label: atorvastatin
    - preferred_term: simvastatin
      term:
        id: NCIT:C29454
        label: Simvastatin
  target_mechanisms:
  - target: Reduced Hepatic Clearance of Circulating LDL Particles
    treatment_effect: RESTORES
    description: >-
      Statin therapy partially restores hepatic LDL clearance in PCSK9
      gain-of-function carriers - serum cholesterol falls, but stays above the
      level reached by LDLR-mutation heterozygotes on the same drugs.
    evidence:
    - reference: PMID:16224054
      reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1+/-3.0 versus 6.5+/-0.9 mmol/L; P=0.006)"
      explanation: >-
        Shows that statin therapy lowers cholesterol in PCSK9 carriers but
        leaves them above the level reached by LDLR-mutation heterozygotes -
        partial restoration, hence PARTIAL.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adults: pharmacotherapy (statins with additional medications as needed) to reduce lipid levels; referral to a lipid specialist if necessary to reduce LDL-C levels"
    explanation: GeneReviews states statins as first-line pharmacotherapy in FH.
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Children: referral to a lipid specialist; diet and lifestyle modifications; statins can be used in children starting around age eight years."
    explanation: >-
      GeneReviews sets the paediatric starting point for statin therapy, which
      matters here because the LDL burden is present from birth.
  notes: >-
    GeneReviews records that statins are contraindicated in pregnancy because
    of teratogenicity concerns and should be discontinued before conception,
    and that the safety of PCSK9 inhibitors, ezetimibe, lomitapide and
    bempedoic acid in pregnancy has not been well studied - so no
    lipid-lowering option is established for a pregnant ADH3 carrier.
- name: Ezetimibe
  description: >-
    Cholesterol-absorption inhibitor added to statin therapy when the LDL-C
    target is not reached. It is step two of the standard FH escalation, before
    a PCSK9-directed agent; it does not act on the PCSK9 lesion itself but
    lowers the LDL burden the lesion creates.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ezetimibe
      term:
        id: CHEBI:49040
        label: ezetimibe
  target_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    treatment_effect: MODULATES
    description: >-
      Reduced intestinal cholesterol absorption lowers the plasma LDL burden
      downstream of the PCSK9 lesion rather than correcting it.
    evidence:
    - reference: PMID:25282519
      reference_title: "PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol."
      explanation: >-
        Places ezetimibe in the FH treatment sequence while making explicit
        that statin plus ezetimibe is often not sufficient - hence PARTIAL.
  notes: >-
    Curated as background therapy for FH generally. No PCSK9-genotyped
    ezetimibe trial is cited.
- name: Bempedoic Acid
  description: >-
    Oral ATP citrate lyase inhibitor that blocks cholesterol synthesis upstream
    of HMG-CoA reductase. Because it is a prodrug activated by a liver-specific
    enzyme absent from skeletal muscle, it is the guideline option for patients
    who cannot tolerate statins - a common situation in FH, where lifelong
    high-intensity statin therapy is the default. Like statins and ezetimibe it
    lowers the LDL burden the PCSK9 lesion creates rather than correcting the
    lesion itself.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bempedoic acid
      term:
        id: CHEBI:149601
        label: bempedoic acid
  target_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    treatment_effect: MODULATES
    description: >-
      ATP citrate lyase inhibition reduces hepatic cholesterol synthesis and so
      lowers the circulating LDL burden downstream of the PCSK9 lesion, without
      acting on PCSK9 or on LDL receptor degradation.
    evidence:
    - reference: PMID:36876740
      reference_title: "Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events"
      explanation: >-
        States the molecular target and the LDL-lowering effect that place this
        agent on the plasma-LDL node rather than on the PCSK9 node.
  evidence:
  - reference: PMID:36876740
    reference_title: "Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004)"
    explanation: >-
      CLEAR Outcomes provides the cardiovascular outcome evidence that
      justifies curating bempedoic acid alongside ezetimibe and apheresis
      rather than as an investigational option.
  notes: >-
    Curated as background therapy for FH generally, on the same footing as
    ezetimibe. CLEAR Outcomes enrolled statin-intolerant patients at high
    cardiovascular risk, not a PCSK9-genotyped or FH-only cohort, so the
    outcome benefit is not ADH3-specific evidence.
- name: LDL Apheresis
  description: >-
    Extracorporeal removal of apoB-containing lipoproteins from plasma,
    reserved for carriers whose LDL-C remains dangerously high on maximal drug
    therapy. Two of the thirteen PCSK9 D374Y carriers in the long-term British
    follow-up required LDL apheresis (one also partial ileal bypass), which is
    the most direct evidence available that this severity of intervention is
    sometimes needed in ADH3 specifically.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: therapeutic apheresis
    term:
      id: NCIT:C173286
      label: Therapeutic Apheresis
  target_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    treatment_effect: MODULATES
    description: >-
      Apheresis removes circulating LDL directly, bypassing the failed hepatic
      receptor route rather than repairing it.
    evidence:
    - reference: PMID:16224054
      reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0+/-1.6 versus 5.4+/-1.0 mmol/L; P=0.001)"
      explanation: >-
        Documents LDL apheresis being used in PCSK9 D374Y carriers as part of
        the therapy needed to control their cholesterol.
  evidence:
  - reference: PMID:16224054
    reference_title: "Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications."
    explanation: >-
      Supports escalation to aggressive lipid-lowering management in this
      genotype, of which apheresis is the most intensive form.
- name: Cardiovascular Risk Factor Modification
  description: >-
    Non-pharmacological management: smoking cessation, reduced saturated and
    trans fat intake, increased soluble fibre, physical activity, weight
    control, and treatment of hypertension and diabetes. These do not address
    the PCSK9 lesion but reduce the atherogenic burden it acts upon.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: lifestyle and risk-factor therapy
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Subendothelial Retention of ApoB-Containing Lipoproteins
    treatment_effect: MODULATES
    description: >-
      Risk-factor modification acts on the endothelial-injury and inflammatory
      arm of atherogenesis rather than on the PCSK9-LDL receptor axis.
    evidence:
    - reference: PMID:24404629
      reference_title: "Familial Hypercholesterolemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Agents/circumstances to avoid: Smoking, high intake of saturated and trans unsaturated fat, sedentary lifestyle, obesity, hypertension, and diabetes mellitus."
      explanation: GeneReviews names the modifiable exposures that aggravate atherosclerotic risk in FH.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevention of primary manifestations: Heart-healthy diet (including reduced intake of saturated fat and increased intake of soluble fiber to 10-20 g/day); increased physical activity; no smoking."
    explanation: GeneReviews management recommendation for primary prevention in FH.
experimental_models:
- name: Urine-derived iPSC hepatocyte-like cells from a PCSK9 S127R carrier (HLC-S127R)
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Human induced pluripotent stem cells reprogrammed from urine-derived
    somatic cells of an individual carrying the ADH3 allele PCSK9 S127R,
    differentiated into hepatocyte-like cells. The model reproduces the
    patient's own genotype in the disease-relevant cell type and reads out the
    functional consequence directly as LDL uptake.
  cell_source: Patient-derived (urine somatic cells reprogrammed to iPSC)
  culture_system: Two-dimensional hepatocyte-like cell differentiation
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: hepatocyte-like cell
    term:
      id: CL:0000182
      label: hepatocyte
  publication: PMID:26586530
  modeled_mechanisms:
  - target: Reduced Hepatic Clearance of Circulating LDL Particles
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Hepatocyte-like cells carrying the patient's S127R allele take up 71% less
      LDL than control cells, the cellular readout of this node.
    limitations: >-
      Hepatocyte-like cells derived from iPSC are immature relative to adult
      hepatocytes; the comparison is between individuals rather than between
      isogenic corrected and uncorrected lines, so donor background is not
      controlled.
    readouts:
    - name: LDL uptake by hepatocyte-like cells
      target: Reduced Hepatic Clearance of Circulating LDL Particles
      direction: DECREASED
      interpretation: >-
        Direct cellular measurement of the impaired LDL clearance this node
        asserts.
      evidence:
      - reference: PMID:26586530
        reference_title: "Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake"
        explanation: Reports the LDL-uptake measurement grounding this readout.
    evidence:
    - reference: PMID:26586530
      reference_title: "Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL."
      explanation: >-
        States the model's purpose as a model of PCSK9-mediated autosomal
        dominant hypercholesterolemia.
  evidence:
  - reference: PMID:26586530
    reference_title: "Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function."
    explanation: The authors' conclusion on the model's utility for studying PCSK9 variant function.
  notes: >-
    The same study reports that pravastatin increased LDL uptake more in
    HLC-S127R than in control cells, matching the good statin response of the
    S127R carriers in the corresponding family - a rare instance of an in vitro
    model tracking a genotype-specific clinical treatment response.
datasets:
- accession: geo:GSE75545
  title: >-
    Urine-sample-derived human induced pluripotent stem cells as a model to
    study PCSK9-mediated autosomal dominant hypercholesterolemia
  description: >-
    Microarray expression data from urine-derived iPSC lines and
    hepatocyte-like cells of a PCSK9 S127R autosomal dominant
    hypercholesterolemia carrier, a PCSK9 loss-of-function
    (familial hypobetalipoproteinemia) carrier, and controls. Manually
    relevance-triaged: the series is about PCSK9-mediated ADH by name and
    genotype, not merely about the PCSK9 gene.
  data_type: MICROARRAY
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:26586530
  notes: >-
    Surfaced by `just discover-datasets` as a DIRECT candidate and confirmed
    against the linked publication before inclusion. Carries no `evidence:`
    block by the dataset-curation SOP.
animal_models:
- name: AAV-hPCSK9(D374Y) mouse
  species: Mouse
  genotype: Liver-directed AAV transfer of human PCSK9 p.Asp374Tyr into wild-type mice
  background: C57BL/6J, 129/SvPasCrlf, or FVB/NCrl
  publication: PMID:25341796
  description: >-
    A single systemic AAV injection delivers the human D374Y gain-of-function
    allele to mouse liver, producing sustained hyperlipidaemia and, on a
    high-fat diet, aortic atherosclerotic lesions with macrophage infiltration
    and fibrous cap formation. Because the disease allele is the human one and
    is expressed in the correct organ, this model reproduces the ADH3 mechanism
    rather than merely a hypercholesterolaemic state.
  genes:
  - preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  evidence:
  - reference: PMID:25341796
    reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Single intravenous AAV-PCSK9(DY) injection is a fast, easy, and cost-effective approach, resulting in rapid and long-term sustained hyperlipidemia and atherosclerosis."
    explanation: >-
      The authors' summary of what the model produces, supporting its use as a
      model of PCSK9 gain-of-function hypercholesterolemia and atherosclerosis.
  modeled_mechanisms:
  - target: Chronic Elevation of Plasma LDL Cholesterol
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Liver expression of human PCSK9 D374Y produces long-term elevation of
      serum LDL in three mouse backgrounds.
    limitations: >-
      Expression is achieved by somatic AAV transfer in adult animals rather
      than by a germline heterozygous allele from conception, so the lifelong
      "cholesterol-years" exposure central to the human disease is not
      reproduced; a high-fat diet is required for lesion development.
    readouts:
    - name: Serum low-density lipoprotein
      target: Chronic Elevation of Plasma LDL Cholesterol
      direction: INCREASED
      interpretation: Direct biochemical correlate of the human LDL-C elevation node.
      evidence:
      - reference: PMID:25341796
        reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "mice in the C57BL/6J, 129/SvPasCrlf, or FVB/NCrl backgrounds developed long-term hyperlipidemia with a strong increase in serum low-density lipoprotein."
        explanation: Reports the LDL measurement grounding this readout.
    evidence:
    - reference: PMID:25341796
      reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We aimed to stably express the pathological human D374Y gain-of-function mutant form of PCSK9 (PCSK9(DY)) in adult wild-type mice to generate a hyperlipidemic and proatherogenic animal model, achieved with a single systemic injection with adeno-associated virus (AAV)."
      explanation: >-
        States that the model expresses the human ADH3 disease allele to
        reproduce the hyperlipidaemic, proatherogenic state.
  - target: Smooth Muscle Cell Switching and Fibrofatty Plaque Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      High-fat-fed AAV-PCSK9(D374Y) mice develop aortic atherosclerotic lesions
      that progress to macrophage-infiltrated, fibrous-capped plaques.
    limitations: >-
      Mouse atherosclerosis reproduces lesion initiation and fibrous-cap
      formation but not the late human complications of plaque rupture and
      thrombosis; lesions are aortic rather than coronary, and a high-fat diet
      is required.
    readouts:
    - name: Aortic atherosclerotic lesion burden and fibrous cap formation
      target: Smooth Muscle Cell Switching and Fibrofatty Plaque Formation
      direction: INCREASED
      interpretation: Histological correlate of the fibrofatty plaque node.
      evidence:
      - reference: PMID:25341796
        reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Advanced lesions in these high-fat-diet-fed mice also showed evidence of macrophage infiltration and fibrous cap formation."
        explanation: Reports the histological lesion features grounding this readout.
    evidence:
    - reference: PMID:25341796
      reference_title: "Induction of sustained hypercholesterolemia by single adeno-associated virus-mediated gene transfer of mutant hPCSK9."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Macroscopic and histological analysis showed atherosclerotic lesions in the aortas of AAV-PCSK9(DY) mice fed a high-fat-diet."
      explanation: Establishes that the model develops atherosclerotic lesions attributable to the PCSK9 D374Y allele.
- name: D374Y-PCSK9 transgenic Yucatan minipig
  species: Pig
  genotype: Liver-specific expression of human PCSK9 p.Asp374Tyr (Sleeping Beauty transposition, somatic cell nuclear transfer)
  background: Yucatan minipig
  publication: PMID:23283366
  description: >-
    Cloned Yucatan minipigs expressing human D374Y-PCSK9 in liver show reduced
    hepatic LDL receptor levels, impaired LDL clearance, severe
    hypercholesterolaemia, and spontaneous progressive atherosclerosis at a
    body size that permits intravascular imaging. The model covers the ADH3
    chain from hepatic receptor loss through to arterial lesion formation; the
    late human events of plaque rupture and atherothrombosis are not
    demonstrated in it.
  genes:
  - preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  evidence:
  - reference: PMID:23283366
    reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This model should prove useful for several types of translational research in atherosclerosis."
    explanation: >-
      The authors' own framing of the model's translational scope, supporting
      its inclusion as an informative model of this disease.
  modeled_mechanisms:
  - target: Reduced Hepatic Clearance of Circulating LDL Particles
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Transgenic pigs show the receptor-depletion-to-clearance-failure step
      directly, with both hepatic LDL receptor level and LDL clearance measured
      in the same animals.
    limitations: >-
      The human allele is expressed from a transgene under a liver-specific
      promoter rather than from the endogenous porcine locus, so expression
      level and regulation need not match a human heterozygote.
    readouts:
    - name: Hepatic LDL receptor level
      target: Reduced Hepatic Clearance of Circulating LDL Particles
      direction: DECREASED
      interpretation: Confirms that the transgene depletes the hepatic receptor pool in vivo.
      evidence:
      - reference: PMID:23283366
        reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."
        explanation: Reports the receptor-level and clearance measurements grounding this readout.
    evidence:
    - reference: PMID:23283366
      reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9."
      explanation: Describes the construction of the model on the human ADH3 allele.
  - target: Smooth Muscle Cell Switching and Fibrofatty Plaque Formation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The pigs develop spontaneous, progressive atherosclerotic lesions without
      the extreme dietary manipulation mouse models require, at a scale and
      pathology closer to human disease.
    limitations: >-
      Even in this model the late human events of plaque rupture and
      atherothrombosis are not established; lesion progression, not acute
      coronary syndrome, is what is demonstrated.
    readouts:
    - name: Progressive atherosclerotic lesion development on noninvasive imaging
      target: Smooth Muscle Cell Switching and Fibrofatty Plaque Formation
      direction: INCREASED
      interpretation: Imaging correlate of arterial plaque formation driven by the PCSK9 gain-of-function allele.
      evidence:
      - reference: PMID:23283366
        reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging."
        explanation: Reports the imaging readout of lesion progression.
    evidence:
    - reference: PMID:23283366
      reference_title: "Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans."
      explanation: >-
        States the human disease claim the model was built to reproduce,
        supporting its relevance to this atherogenesis node.
clinical_trials:
- name: NCT01763918
  phase: PHASE_III
  status: COMPLETED
  description: >-
    RUTHERFORD-2: randomised, double-blind, placebo-controlled trial of
    evolocumab in adults with heterozygous familial hypercholesterolemia on
    stable lipid-lowering therapy.
  target_phenotypes:
  - preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - reference: clinicaltrials:NCT01763918
    reference_title: "A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 on LDL-C in Subjects With Heterozygous Familial Hypercholesterolemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary objective was to evaluate the effect of 12 weeks of evolocumab subcutaneously once every 2 weeks (Q2W) and once monthly (QM), compared with placebo, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in adults with heterozygous familial hypercholesterolemia (HeFH)."
    explanation: >-
      Registration record establishing the trial's population (heterozygous FH)
      and LDL-C endpoint.
- name: NCT05398029
  phase: PHASE_I
  status: RECRUITING
  description: >-
    VT-1001 (VERVE-101): open-label phase 1b single-ascending-dose study of a
    liver-directed base editor designed to disrupt PCSK9 expression, in
    heterozygous familial hypercholesterolemia with atherosclerotic
    cardiovascular disease. Included because it targets the PCSK9 node of this
    disease's pathograph directly; it is an early-phase safety study, not
    evidence of efficacy.
  target_phenotypes:
  - preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - reference: clinicaltrials:NCT05398029
    reference_title: "Open-label, Phase 1b, Single-ascending Dose and Optional re Dosing Study to Evaluate the Safety of VERVE-101 Administered to Patients With Heterozygous Familial Hypercholesterolemia, Atherosclerotic Cardiovascular Disease, and Uncontrolled Hypercholesterolemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VERVE-101 uses base-editing technology designed to disrupt the expression of the PCSK9 gene in the liver and lower circulating PCSK9 and LDL-C in patients with established ASCVD due to HeFH."
    explanation: >-
      Registration record establishing that the intervention acts on hepatic
      PCSK9 expression, the mechanism node of this entry.
- name: NCT03397121
  phase: PHASE_III
  status: COMPLETED
  description: >-
    ORION-9: placebo-controlled, double-blind, randomised trial of twice-yearly
    inclisiran sodium in adults with heterozygous familial hypercholesterolemia
    and elevated LDL cholesterol.
  target_phenotypes:
  - preferred_term: Increased LDL cholesterol concentration
    term:
      id: HP:0003141
      label: Increased LDL cholesterol concentration
  evidence:
  - reference: clinicaltrials:NCT03397121
    reference_title: "Placebo-Controlled, Double-Blind, Randomized Trial to Evaluate the Effect of 300 mg of Inclisiran Sodium Given as Subcutaneous Injections in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH) and Elevated Low-Density Lipoprotein Cholesterol (LDL-C)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a Phase III, placebo-controlled, double-blind, randomized study in participants with HeFH and elevated LDL-C to evaluate the efficacy, safety, and tolerability of subcutaneous (SC) injection(s) of inclisiran."
    explanation: >-
      Registration record establishing the trial's population and the
      intervention relevant to this disease.
- name: NCT05465278
  phase: PHASE_IV
  status: COMPLETED
  description: >-
    ARCHITECT: open-label multicentre study of alirocumab in molecularly
    diagnosed familial hypercholesterolemia from the SAFEHEART registry, with
    coronary CT angiography assessment of plaque volume, architecture, and
    composition. Included specifically because its cohort is genetically
    confirmed rather than clinically defined, which is the caveat the treatment
    entries in this file repeatedly flag; and because its endpoint is
    atherosclerotic plaque - the pathophysiology nodes downstream of the LDL
    node - rather than LDL-C alone.
  target_phenotypes:
  - preferred_term: Coronary artery atherosclerosis
    term:
      id: HP:0001677
      label: Coronary artery atherosclerosis
  evidence:
  - reference: clinicaltrials:NCT05465278
    reference_title: "Clinical Trial to Evaluate the Effect of Alirocumab on the Volume, Architecture and Composition of Atherosclerotic Plaque in Patients With Familial Hypercholesterolemia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical trial to evaluate the effect of alirocumab on the volume, architecture and composition of atherosclerotic plaque in patients with Familial hypercholesterolemia from the SAFEHEART Registry"
    explanation: >-
      Registration record establishing the intervention, the plaque endpoint,
      and the registry-based FH cohort.
  notes: >-
    The registry record does not itself state that participants are molecularly
    diagnosed; that characterisation comes from the SAFEHEART registry's own
    genetic-confirmation entry requirement and is not curated here as an
    evidenced claim.
diagnosis:
- name: Molecular Genetic Testing of PCSK9
  description: >-
    ADH3 is distinguished from the other dominant forms of familial
    hypercholesterolemia only by molecular testing; the clinical and
    biochemical picture overlaps LDLR- and APOB-related FH. Identification of a
    heterozygous gain-of-function PCSK9 variant establishes the diagnosis and
    enables cascade screening of relatives.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."
    explanation: >-
      GeneReviews states that molecular identification of a gain-of-function
      PCSK9 variant establishes the molecular diagnosis.
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing is the preferred method for clarifying the diagnosis in at-risk family members, when possible."
    explanation: >-
      GeneReviews states that molecular testing is the preferred route for
      cascade clarification in relatives, the claim made in this entry's
      description.
- name: Lipid Surveillance from Early Childhood
  description: >-
    Because the LDL-C elevation is present from birth, GeneReviews recommends
    monitoring lipid levels from age two years and identifying modifiable
    cardiovascular risk factors, so that treatment can start at the point of
    greatest cumulative benefit.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Monitor lipid levels from age two years; consider noninvasive imaging modalities in adults; identify modifiable risk factors (e.g., smoking, sedentary behavior, hypertension, diabetes, obesity)."
    explanation: GeneReviews surveillance recommendation for FH.
- name: Clinical Diagnostic Criteria for Familial Hypercholesterolemia
  description: >-
    Before molecular testing, patients reach an FH diagnosis through validated
    phenotypic frameworks - the Dutch Lipid Clinic Network (DLCN), Simon Broome,
    and MEDPED criteria - which score untreated LDL-C together with tendon
    xanthomas, corneal arcus, and personal or family history of premature
    coronary disease. These are FH-wide instruments: they identify a clinical FH
    phenotype but cannot distinguish ADH3 from LDLR- or APOB-related FH, which
    is why a positive clinical score is the trigger for the PCSK9 molecular
    testing curated above rather than a substitute for it. They are also
    imperfect at predicting a mutation at all, and lipoprotein(a) cholesterol
    counted inside the measured LDL-C inflates them in a substantial minority of
    scored patients.
  evidence:
  - reference: PMID:29408959
    reference_title: "A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED), and American Heart Association (AHA) criteria in predicting an FH-causing mutation."
    explanation: >-
      Names the three clinical criteria sets used to reach an FH diagnosis
      before genetic testing.
  - reference: PMID:29408959
    reference_title: "A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate."
    explanation: >-
      PARTIAL because the sentence that validates the criteria also records
      their limitation - only moderate concordance - which is why this entry
      keeps molecular testing as the diagnostic step.
  notes: >-
    Curated as the FH-wide clinical route into the diagnosis, not as an
    ADH3-specific instrument. None of DLCN, Simon Broome, or MEDPED contains a
    gene-level criterion that would separate PCSK9 from LDLR or APOB disease.
differential_diagnoses:
- name: Familial hypercholesterolemia due to LDLR variants
  description: >-
    The most common dominant FH form. Clinically indistinguishable from ADH3 at
    the bedside; distinguished by molecular testing. Mechanistically the
    receptor itself is defective, rather than being degraded prematurely by a
    normal-but-overactive regulator.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."
    explanation: >-
      GeneReviews lists LDLR alongside PCSK9 as an alternative molecular cause
      of the same clinical picture, which is what makes it a differential.
- name: Familial defective apolipoprotein B-100 (APOB)
  description: >-
    Dominant FH caused by APOB variants that impair binding of LDL to the LDL
    receptor. The receptor and its regulation are intact; the ligand is
    defective.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular diagnosis of FH can be established by identification of heterozygous or biallelic pathogenic variants in APOB (variants that impair binding of LDL-C to the LDL receptor), LDLR, or PCSK9 (gain of function); or rarely, identification of biallelic pathogenic variants in LDLRAP1."
    explanation: >-
      GeneReviews specifies the APOB mechanism (impaired binding of LDL-C to the
      receptor) that distinguishes it from PCSK9 gain of function.
- name: Autosomal recessive hypercholesterolemia (LDLRAP1)
  description: >-
    Caused by biallelic LDLRAP1 variants affecting the adaptor required for
    receptor endocytosis; recessive rather than dominant inheritance.
  evidence:
  - reference: PMID:24404629
    reference_title: "Familial Hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LDLRAP1-related FH is caused by biallelic pathogenic variants and is inherited in an autosomal recessive manner."
    explanation: >-
      GeneReviews states the recessive inheritance that separates this entity
      from dominant ADH3.
- name: Polygenic hypercholesterolemia
  description: >-
    Elevated LDL cholesterol from the aggregate effect of many common
    small-effect alleles rather than a single dominant variant; the commonest
    explanation for a clinical FH phenotype without an identified monogenic
    cause.
- name: Sterol storage disorders presenting with tendon xanthomas
  description: >-
    Sitosterolemia (ABCG5/ABCG8) and cerebrotendinous xanthomatosis (CYP27A1)
    both produce tendon xanthomas indistinguishable on inspection from those of
    FH, and lysosomal acid lipase deficiency likewise causes dyslipidaemia with
    lipid deposition. They are separated from ADH3 not by the xanthomas but by
    the sterol profile and by inheritance - both are recessive, and in
    cerebrotendinous xanthomatosis cholesterol may be normal while cholestanol
    accumulates. This matters here because tendon xanthomatosis is a curated
    phenotype of this entry and is one of the strongest predictors in the
    clinical FH criteria above, so a xanthoma phenocopy can score as clinical FH
    while carrying no PCSK9 variant.
  evidence:
  - reference: PMID:27678445
    reference_title: "Tendon xanthomas: Not always familial hypercholesterolemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tendon xanthoma are most commonly associated with Familial Hypercholesterolemia, but the differential diagnosis includes sitosterolemia and cerebrotendinous xanthomatosis (CTX)."
    explanation: >-
      Names the two sterol storage disorders that phenocopy the tendon-xanthoma
      sign of FH.

📚

References & Deep Research

References

1

PMID:24404629

Familial Hypercholesterolemia.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Autosomal Dominant Hypercholesterolemia 3 (ADH3): Disease Characteristics Report

Edison Scientific Literature 48 citations 2026-08-18T21:13:37.170113

Autosomal Dominant Hypercholesterolemia 3 (ADH3): Disease Characteristics Report

Executive summary and evidence boundaries

Autosomal dominant hypercholesterolemia 3 (ADH3; FH3) is the rare PCSK9 gain-of-function (GOF) subtype of familial hypercholesterolemia (FH). Pathogenic monoallelic PCSK9 variants increase hepatic LDL-receptor (LDLR) degradation, causing lifelong elevation of LDL cholesterol (LDL-C), accelerated atherosclerosis, and premature coronary artery disease (CAD). The defining human discovery was reported by Abifadel et al. in June 2003, Nature Genetics, “Mutations in PCSK9 cause autosomal dominant hypercholesterolemia” (PMID 12730697; DOI: https://doi.org/10.1038/ng1161). Open Targets independently maps ADH3 to MONDO:0011369 and PCSK9 (ENSG00000169174), with human genetic and approved-therapy evidence. (OpenTargets Search: familial hypercholesterolemia-PCSK9)

A major curation caveat is that most epidemiology, outcomes, diagnostic thresholds, and treatment trials pool all molecular forms of heterozygous FH—predominantly LDLR-related disease. Such findings are identified below as FH-wide, not ADH3-specific. Direct ADH3 evidence consists principally of families carrying PCSK9 GOF variants, biochemical studies, and PCSK9-GOF animal models.

The following table provides a compact knowledge-base representation.

Domain	Summary	Key IDs / ontology suggestions	Evidence qualifier
Identity / identifiers	Autosomal Dominant Hypercholesterolemia 3 (ADH3) is the PCSK9-related monogenic form of familial hypercholesterolemia; evidence here is disease-level, aggregated from databases, guidelines, trials, and literature rather than individual EHR records.	MONDO:0011369; MeSH disease family terms in trial metadata include Hypercholesterolemia/Hyperlipoproteinemia Type II; target gene PCSK9 = ENSG00000169174 (OpenTargets Search: familial hypercholesterolemia-PCSK9, NCT05398029 chunk 1)	Authoritative database + clinical literature; ADH3-specific MONDO supported, but other disease codes were not directly retrieved here.
Causal gene and inheritance	Causal gene: PCSK9; pathogenic gain-of-function alleles cause ADH3/FH3. Inheritance is monoallelic autosomal dominant.	PCSK9; inheritance: autosomal dominant / monoallelic; related FH gene class includes LDLR, APOB, PCSK9 (OpenTargets Search: familial hypercholesterolemia-PCSK9, cesaro2020beyondcholesterolmetabolism pages 1-2, abifadel2023geneticandmolecular pages 1-2)	Strong human genetic evidence; target-disease linkage also supported by drug-approval evidence.
Representative GOF variants	Recurrently cited GOF variants include S127R, F216L, D374Y; additional GOF variants in prodomain and C-terminal CM1/CHR regions impair LDL association and/or enhance LDLR binding/degradation.	Variant examples: p.Ser127Arg, p.Phe216Leu, p.Asp374Tyr, p.Arg496Trp (sarkar2022pathogenicgainoffunctionmutations pages 1-2, sarkar2022pathogenicgainoffunctionmutations pages 2-3, rosenson2019cholesterolloweringagents. pages 5-5)	Variant list is representative, not exhaustive; some classic primary papers were referenced indirectly or unobtainable in-tool.
Core mechanism	PCSK9 is a secreted hepatocyte-enriched protein that binds LDLR and diverts it to endo-lysosomal degradation, reducing receptor recycling and hepatic LDL clearance. GOF variants intensify this process by increasing LDLR affinity and/or altering LDL binding regulation, producing lifelong LDL-C elevation and accelerated atherosclerosis.	GO: LDL receptor catabolic process; GO: receptor-mediated endocytosis; GO CC suggestions: extracellular region, lysosome; CL: hepatocyte; UBERON: liver (rosenson2019cholesterolloweringagents. pages 3-5, sarkar2022pathogenicgainoffunctionmutations pages 2-3, sundararaman2021pcsk9amultifaceted pages 2-4, cesaro2020beyondcholesterolmetabolism pages 1-2)	Human, in vitro, and animal evidence converge; LDLR-independent inflammatory roles are plausible but less disease-defining than hepatic LDLR degradation.
Hallmark phenotypes / HPO suggestions	Hallmarks align with heterozygous familial hypercholesterolemia: markedly elevated LDL-C/hypercholesterolemia, tendon/skin xanthomas, corneal arcus, premature coronary artery disease, premature atherosclerosis; stroke risk less consistently increased than CAD.	HPO suggestions: HP:0003124 Hypercholesterolemia; HP:0000991 Xanthoma; HP:0001084 Corneal arcus; HP:0001677 Coronary artery atherosclerosis; HP:0001716 Premature arteriosclerosis (suggestive) (haradashiba2023guidelinesforthe pages 2-4, fularski2024unveilingfamilialhypercholesterolemia—review pages 1-2, fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9)	Phenotype frequencies were mainly available for FH broadly, not ADH3-only cohorts.
Diagnosis	Diagnosis generally follows FH frameworks: family history, LDL-C level, premature CAD, tendon xanthomas/Achilles tendon thickening, and confirmatory molecular testing. Japanese adult guideline updated Achilles tendon thresholds to ≥8.0 mm men / ≥7.5 mm women to improve sensitivity.	Diagnostic systems: DLCN / Simon Broome / national FH criteria; test target genes include LDLR, APOB, PCSK9; HPO: HP:0003326 Elevated LDL cholesterol concentration (suggestive) (haradashiba2023guidelinesforthe pages 1-2, yip2023geneticspectrumand pages 1-2, fularski2024unveilingfamilialhypercholesterolemia—review pages 1-2)	Clinical diagnosis is usually FH-spectrum; molecular confirmation can specify ADH3.
Treatment algorithm	Stepwise care: lifestyle optimization + high-intensity statin first line; add ezetimibe if needed; add PCSK9 inhibitor (alirocumab/evolocumab) for very-high-risk or insufficient control; inclisiran or bempedoic acid are additional options; lipoprotein apheresis for refractory/severe disease. Typical very-high-risk LDL-C goal: ≥50% reduction and <55 mg/dL (<1.4 mmol/L).	NCIT suggestions: Statin therapy, Ezetimibe, Alirocumab, Evolocumab, Inclisiran, Bempedoic Acid, Lipoprotein Apheresis (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9, damase2024establishedandemerging pages 1-3, katzmann2020pcsk9inhibitioninsights pages 1-2, rajendran2024acomparativeanalysis pages 1-2)	Algorithm is evidence-based for FH broadly; ADH3-specific response data are limited but PCSK9-targeted therapies are mechanistically central.
Epidemiology caveat	No robust prevalence estimate was retrieved for ADH3 specifically. Most published epidemiology concerns all heterozygous FH, estimated around 1:311 to 1:303 in the general population and ~1:17 among ASCVD patients; prevalence varies by ethnicity and founder effects.	Use disease-level caveat flag: “FH-wide estimate, not ADH3-specific”; MONDO:0011369 only identifies subtype (hu2020prevalenceoffamilial pages 11-11, hu2020prevalenceoffamilial pages 1-2, toftnielsen2022familialhypercholesterolemiaprevalence pages 1-3, taranto2023geneticheterogeneityof pages 1-2)	Important limitation for knowledge-base curation: subtype-specific denominators are not established here.
Major trials / real-world implementation	PCSK9-directed implementation includes approved antibodies and emerging gene/RNA approaches. Trial examples: VERVE-101 base editing in HeFH + ASCVD (NCT05398029, phase 1, n=13); pediatric evolocumab extension (NCT02624869, n=163); adolescent inclisiran ORION-16 (NCT04652726, n=141); alirocumab plaque study ARCHITECT (NCT05465278, n=104).	NCT05398029; NCT02624869; NCT04652726; NCT05465278 (NCT05398029 chunk 1, NCT05465278 chunk 1, NCT02624869 chunk 1, NCT04652726 chunk 1)	Demonstrates real-world translation from gene discovery to antibodies, siRNA, and base editing.
Model organisms	Useful disease models include AAV-hPCSK9 D374Y mice causing sustained hypercholesterolemia and atherosclerosis, and Yucatan miniature pigs/minipigs carrying human PCSK9 D374Y with coronary/aortic lesions. A 2024 PCSK9 nanoparticle vaccine used AAV-hPCSK9D374Y mouse models. Limitation: pig models may not reproduce plaque rupture/thrombosis fully.	Species: Mus musculus; Sus scrofa; variant/model driver: PCSK9 D374Y; CL/UBERON relevance: hepatocyte, aorta, coronary artery (rochemolina2015inductionofsustained pages 1-2, perleberg2018geneticallyengineeredpigs pages 4-4, fang2024developmentofa pages 1-3, katsuki2024theroleof pages 7-7)	Strong translational utility for mechanism and therapy testing; imperfect recapitulation of late human plaque complications.

Table: This compact table summarizes the most actionable knowledge-base fields for Autosomal Dominant Hypercholesterolemia 3, emphasizing what is directly supported for the PCSK9-related subtype versus what is only available for familial hypercholesterolemia more broadly.

1. Disease information

Definition and identifiers

ADH3 is a congenital, chronic Mendelian disorder of LDL metabolism caused by monoallelic PCSK9 GOF variants. It is clinically part of heterozygous familial hypercholesterolemia and is characterized by elevated LDL-C from early life, cholesterol deposition in tendons/skin/cornea, and premature atherosclerotic cardiovascular disease (ASCVD).

MONDO: MONDO:0011369, hypercholesterolemia, autosomal dominant, 3.
OMIM: 603776, Hypercholesterolemia, autosomal dominant, 3; causal gene PCSK9, OMIM 607786. These OMIM numbers are standard database mappings but were not directly returned by the retrieved full-text corpus.
Synonyms: ADH3; FH3; PCSK9-related familial hypercholesterolemia; PCSK9-associated autosomal dominant hypercholesterolemia; familial hypercholesterolemia due to PCSK9 GOF.
MeSH umbrella terms: Hypercholesterolemia; Hyperlipoproteinemia Type II; Familial Hypercholesterolemia. Trial metadata maps relevant studies to MeSH Hypercholesterolemia and Hyperlipoproteinemia Type II. (NCT05398029 chunk 1)
ICD: There is generally no dedicated ADH3 code. ICD-10-CM E78.01 represents familial hypercholesterolemia; ICD-11 coding is ordinarily at the familial/pure hypercholesterolemia level rather than PCSK9 subtype. Local verification is advisable before database ingestion.
Data provenance: This report uses aggregated disease-level databases, publications, guidelines, and trial registries—not individual-patient EHR data. Some founding evidence derives from individual pedigrees.

2. Etiology, risk, protection, and gene–environment interaction

Primary cause

The necessary upstream cause is a germline, heterozygous PCSK9 GOF variant. PCSK9 GOF may increase LDLR affinity, secretion or effective activity, impair inhibitory LDL binding, or otherwise augment LDLR degradation. Representative variants are p.Ser127Arg (S127R), p.Phe216Leu (F216L), p.Asp374Tyr (D374Y), and p.Arg496Trp (R496W). S127R, F216L, and D374Y cosegregate with hypercholesterolemia in reported families. (rosenson2019cholesterolloweringagents. pages 5-5, sarkar2022pathogenicgainoffunctionmutations pages 1-2)

Genetic risk and modifiers

The pathogenic PCSK9 allele is the primary risk factor; first-degree relatives have a 50% transmission probability.
Variant-specific function materially affects severity. D374Y increases PCSK9–LDLR affinity by at least tenfold in experimental evidence and is associated with severe disease. (rochemolina2015inductionofsustained pages 1-2)
Polygenic LDL-C burden and variants in other lipid genes can modify FH expression. FH-wide modifier candidates include common-variant polygenic risk scores and genes producing overlapping dyslipidemias. (taranto2023geneticheterogeneityof pages 1-2, taranto2023geneticheterogeneityof pages 2-4)
Elevated lipoprotein(a), diabetes, hypertension, smoking, and established ASCVD increase clinical risk even though they do not cause ADH3.

Protective factors

Genetic: PCSK9 loss-of-function (LOF) alleles lower LDL-C and lifetime ASCVD risk; biallelic human PCSK9 deficiency has been observed with very low LDL-C and no major syndromic phenotype. A UK Biobank burden analysis in Open Targets reported an odds ratio of 0.228 for a PCSK9-LOF association (P=2.25×10⁻¹⁸), although this is protective population evidence, not an ADH3 modifier study. (OpenTargets Search: familial hypercholesterolemia-PCSK9, rosenson2019cholesterolloweringagents. pages 5-5)
Environmental/clinical: avoidance of tobacco, a diet low in saturated/trans fats, exercise, healthy weight, and control of blood pressure/diabetes reduce total cardiovascular risk. They do not normalize the genetically elevated LDL-C and should not replace pharmacotherapy.

Gene–environment interaction

The clinically important interaction is cumulative “cholesterol-years.” A PCSK9 GOF allele raises LDL-C from childhood; smoking, diabetes, hypertension, poor diet, and inactivity add vascular risk, whereas early sustained LDL lowering reduces cumulative arterial exposure. FH-wide analysis estimates that a CHD-producing LDL burden is reached at about 12.5 years in FH versus roughly 55 years without FH. (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9, ray2022worldheartfederation pages 1-2)

No infectious, toxic, occupational, or radiation exposure is established as a cause of ADH3.

3. Phenotypes

Phenotype	Type and characteristics	Suggested HPO term
Elevated LDL-C	Laboratory abnormality; present from childhood, chronic and untreated progressive in cumulative impact; magnitude is variant- and treatment-dependent	HP:0003141 Increased LDL cholesterol concentration
Hypercholesterolemia	Laboratory/diagnostic phenotype, generally highly penetrant but variable	HP:0003124 Hypercholesterolemia
Tendon xanthoma	Physical sign; usually develops after prolonged exposure and may be absent, especially in young or screen-detected people	HP:0001052 Xanthomatosis / HP:0000991 Xanthoma
Xanthelasma/skin xanthoma	Physical manifestation; age-dependent and non-obligate	HP:0000493 Xanthelasma
Corneal arcus	Physical sign, especially significant when premature	HP:0001084 Corneal arcus
Premature coronary atherosclerosis/CAD	Major progressive complication; adult onset is usual in heterozygous disease but can occur earlier with severe variants	HP:0001677 Coronary artery atherosclerosis; HP:0001701 Angina pectoris
Myocardial infarction	Clinical complication of plaque disruption/ischemia	HP:0001658 Myocardial infarction
Peripheral arterial disease	Less frequent than CAD but FH-wide risk is elevated	HP:0004950 Peripheral arterial disease

FH-wide guidelines report untreated CAD onset commonly at 30–50 years in men and 50–70 years in women, a 10–20-fold CAD risk relative to unaffected populations, and approximately 13-fold excess CAD risk in untreated heterozygous FH. Stroke association is less consistent. (haradashiba2023guidelinesforthe pages 2-4)

Published ADH3-only phenotype frequencies and validated quality-of-life estimates are not available from the retrieved evidence. Quality of life is affected indirectly through anxiety regarding inherited risk, lifelong medication/injections, dietary burden, screening, premature angina/MI, and procedural treatment. Screen-detected relatives may initially be asymptomatic; a 2023 Hong Kong study found cascade-detected adults had milder phenotypes than probands. (yip2023geneticspectrumand pages 1-2)

4. Genetic and molecular information

Gene and protein

PCSK9: HGNC 20001; Ensembl ENSG00000169174; chromosome 1p32.3.
Protein: 692-aa secreted proprotein convertase with signal peptide, prodomain, catalytic domain, hinge, and C-terminal cysteine/histidine-rich domain. After autocleavage, the prodomain remains attached; LDLR degradation does not require further proteolytic activity because PCSK9 functions principally as a trafficking chaperone. (sarkar2022pathogenicgainoffunctionmutations pages 2-3, sundararaman2021pcsk9amultifaceted pages 2-4, cesaro2020beyondcholesterolmetabolism pages 1-2)

Representative pathogenic variants

p.Ser127Arg: prodomain missense GOF; nearly abolishes LDL binding, removing LDL-mediated inhibition of PCSK9 action. Direct in-vitro evidence showed that “LDL binding was nearly abolished” by S127R. (sarkar2022pathogenicgainoffunctionmutations pages 1-2)
p.Phe216Leu: missense GOF, cosegregating with FH in a French family; reported mechanisms include enhanced PCSK9 function/secretion.
p.Asp374Tyr: catalytic-domain missense GOF; markedly increases affinity for the LDLR EGF-A domain and produces a severe phenotype. (sarkar2022pathogenicgainoffunctionmutations pages 2-3, rochemolina2015inductionofsustained pages 1-2)
p.Arg496Trp: C-terminal CM1-domain missense GOF that inhibits LDL association. (sarkar2022pathogenicgainoffunctionmutations pages 1-2)

These are germline, not somatic, variants. Population allele frequencies are expected to be very rare and should be extracted per genomic build and transcript directly from gnomAD/ClinVar. No single frequency can safely represent all variants. Classification should use current ClinVar/ClinGen assertions and ACMG/AMP criteria; not every PCSK9 missense variant is pathogenic.

Other genomic fields

No recurrent aneuploidy, translocation, repeat expansion, mitochondrial variant, or disease-defining epigenetic lesion is established. Germline mosaicism and anticipation are not recognized characteristic mechanisms. Modifier genes/PRS may alter severity, but no ADH3-specific modifier has sufficient evidence for routine clinical annotation. (taranto2023geneticheterogeneityof pages 1-2)

5. Environmental information

ADH3 is not environmentally caused. Saturated-fat intake, obesity, inactivity, smoking, diabetes, hypertension, and possibly high Lp(a) amplify LDL burden or vascular consequences. Exercise, cardioprotective diet, weight control, and tobacco avoidance are supportive risk-reduction measures. No pathogen, toxin, pollution exposure, or occupational agent is known to initiate the Mendelian disorder.

6. Mechanism and pathophysiology

Causal chain

Upstream genetic trigger: monoallelic PCSK9 GOF variant.
Protein-level effect: increased PCSK9 activity/LDLR affinity or loss of normal LDL-mediated restraint.
Cellular effect: secreted PCSK9 binds LDLR on hepatocytes and directs the PCSK9–LDLR complex to endosomes/lysosomes rather than allowing receptor recycling.
Metabolic effect: fewer surface LDLRs reduce hepatic receptor-mediated LDL uptake, increasing plasma LDL-C and apoB-particle residence time.
Tissue injury: LDL enters the arterial intima, undergoes modification, and drives macrophage foam-cell formation, inflammation, smooth-muscle responses, necrotic-core formation, and fibrous plaque.
Clinical expression: xanthomas/corneal lipid deposition and premature CAD, MI, and peripheral arterial disease. (rosenson2019cholesterolloweringagents. pages 3-5, sarkar2022pathogenicgainoffunctionmutations pages 2-3, cesaro2020beyondcholesterolmetabolism pages 1-2)

PCSK9 may additionally promote macrophage activation through lipid-dependent and LDLR-independent pathways. Proposed downstream pathways include ApoER2 degradation, NF-κB activation, and increased TNF-α, IL-1β, and IL-6. These pleiotropic mechanisms are biologically plausible but less firmly established as necessary causes of ADH3 than hepatic LDLR degradation. A 2024 expert review notes that PCSK9 inhibitors reduce events without clearly reducing systemic hs-CRP, arguing against overinterpreting systemic anti-inflammatory effects. (rosenson2019cholesterolloweringagents. pages 3-5, katsuki2024theroleof pages 1-2)

Suggested ontology annotations

GO biological process: receptor-mediated endocytosis (GO:0006898); cholesterol homeostasis (GO:0042632); regulation of plasma lipoprotein-particle levels (GO:0097006); low-density lipoprotein particle clearance (GO:0034383); lysosomal protein catabolic process (GO:1905146); inflammatory response (GO:0006954); foam-cell differentiation (GO:0050727).
GO cellular component: extracellular region (GO:0005576); plasma membrane (GO:0005886); endosome (GO:0005768); lysosome (GO:0005764); endoplasmic reticulum (GO:0005783); Golgi apparatus (GO:0005794).
Cell Ontology: hepatocyte (CL:0000182), macrophage (CL:0000235), endothelial cell (CL:0000115), vascular-associated smooth-muscle cell (CL:0000359), dendritic cell (CL:0000451), T cell (CL:0000084).

Molecular profiling and advanced technology

No validated ADH3-specific diagnostic transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic signature was identified. The actionable molecular profile remains high LDL-C plus a pathogenic PCSK9 GOF allele. Human iPSC hepatocyte and organoid platforms are increasingly useful for lipoprotein biology, but retrieved patient-specific work primarily modeled LDLR-null FH, not ADH3. Consequently, these technologies should be annotated as emerging research platforms rather than established ADH3 diagnostics.

7. Anatomical structures affected

Primary metabolic organ: liver—hepatocytes synthesize most circulating PCSK9 and clear LDL through LDLR. Suggested UBERON: liver UBERON:0002107.
Primary injured system: arterial tree, especially coronary arteries and aorta; carotid and peripheral arteries may also be involved. Suggested terms: artery UBERON:0001637, aorta UBERON:0000947, coronary artery UBERON:0001621.
Secondary deposits: Achilles and other tendons, skin, eyelids, and corneal periphery.
Subcellular sites: ER/Golgi for PCSK9 synthesis and secretion; plasma membrane for LDLR binding; endosome/lysosome for receptor degradation.
Laterality: systemic and generally bilateral/non-lateralized; coronary lesions are anatomically heterogeneous rather than predictably unilateral.

8. Temporal development

The molecular phenotype begins at or before birth because the variant is constitutional, although clinical signs are often absent in childhood. LDL-C elevation is stable/chronic; arterial damage is slowly progressive and proportional to cumulative exposure. Tendon xanthomas and corneal arcus are age-dependent. Untreated clinical CAD generally emerges in adulthood, earlier in men and in severe GOF variants. The disease is lifelong, without spontaneous remission. Treatment can normalize or greatly reduce LDL-C and stabilize/regress plaque but does not remove the inherited allele. The critical intervention period is childhood or as soon after diagnosis as possible. FH guidance recommends statins around ages 8–10 years, with pediatric targets individualized by risk. (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9)

9. Inheritance and population

ADH3 is autosomal dominant, affecting all sexes. Penetrance is high for LDL-C elevation but age-dependent and incompletely quantified for each variant; clinical ASCVD penetrance is incomplete because it depends on variant effect, treatment, sex, age, Lp(a), and conventional risk factors. Expressivity is variable. Anticipation and a consanguinity requirement are not expected. Homozygosity or compound genetic states can produce much more severe FH, but this is exceptionally rare.

There is no robust ADH3-specific prevalence or incidence estimate. FH-wide meta-analysis of 62 studies and >7.3 million people estimated heterozygous FH prevalence at 1:311 (95% CI 1:250–1:397), about 25 million people globally, and 1:17 among ASCVD populations. (hu2020prevalenceoffamilial pages 11-11, hu2020prevalenceoffamilial pages 1-2) A separate meta-analysis estimated 0.33% (1:303), ranging from 1:192 among Black participants to 1:400 among Asian participants; these are all-gene FH estimates affected by ascertainment and founder effects and must not be assigned directly to ADH3. (toftnielsen2022familialhypercholesterolemiaprevalence pages 1-3)

10. Diagnostics

Clinical evaluation

Repeat fasting or nonfasting lipid profile: total cholesterol, calculated/direct LDL-C, HDL-C, triglycerides, non-HDL-C, apoB; measure Lp(a) at least once.
Document pretreatment LDL-C, premature CAD, tendon/skin xanthomas, corneal arcus, and three-generation family history.
Exclude secondary hypercholesterolemia: hypothyroidism, nephrotic syndrome, cholestatic liver disease, uncontrolled diabetes, medications, and diet-related dyslipidemia.
Apply a validated FH framework such as Dutch Lipid Clinic Network, Simon Broome, MEDPED, or national criteria.
Assess vascular burden as clinically indicated: ECG/stress testing, coronary CT angiography or calcium assessment, carotid ultrasound, and Achilles-tendon radiography/ultrasound. Japanese 2023 guidance uses Achilles thresholds of ≥8.0 mm in men and ≥7.5 mm in women. (haradashiba2023guidelinesforthe pages 1-2)

Genetic testing

Preferred testing is an FH panel containing LDLR, APOB, PCSK9, LDLRAP1, and often APOE plus phenocopy genes ABCG5, ABCG8, LIPA, CYP27A1. Sequence and deletion/duplication analysis should be included. A pathogenic/likely pathogenic PCSK9 GOF variant establishes molecular ADH3 and enables targeted cascade testing. (taranto2023geneticheterogeneityof pages 1-2)

Single-gene PCSK9 testing is appropriate when a familial variant is known. WES/WGS is useful for unresolved severe or atypical cases but is not first-line when a validated panel is available. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine. RNA-seq may help resolve selected splice variants but is not standard diagnosis.

Differential diagnoses include LDLR-FH1, APOB-FH2, autosomal-recessive LDLRAP1 disease, polygenic hypercholesterolemia, sitosterolemia, cerebrotendinous xanthomatosis, lysosomal-acid-lipase deficiency, familial combined hyperlipidemia, and secondary hypercholesterolemia.

Cascade screening is a high-value real-world application. In a 2023 Hong Kong series, 31 probands plus 15 relatives were tested; cascade-detected adults had less severe phenotypes and would often have missed local testing criteria. (yip2023geneticspectrumand pages 1-2)

11. Outcomes and prognosis

Untreated prognosis is dominated by premature CAD/MI. FH-wide historical data reported cardiac death in 73% of men and 64% of women, with mean death age around 63 years before statins; mean age increased to 76 years after statin availability. These figures are historical FH-wide estimates, not ADH3-specific survival rates. (haradashiba2023guidelinesforthe pages 1-2)

Prognostic factors include cumulative untreated LDL-C, PCSK9 variant severity, age at treatment, achieved LDL-C, smoking, male sex at younger ages, diabetes, hypertension, Lp(a), and existing ASCVD. There is no validated ADH3-specific 5- or 10-year survival model. Recovery from the genotype does not occur, but cardiovascular excess risk is substantially modifiable through early sustained LDL reduction.

12. Treatment

Current algorithm

Lifestyle and adherence support for every patient.
High-intensity statin—atorvastatin or rosuvastatin—as first-line therapy. Atorvastatin 80 mg can reduce LDL-C by about 50%. (damase2024establishedandemerging pages 1-3)
Add ezetimibe if the target is not reached.
Add a PCSK9 monoclonal antibody, alirocumab or evolocumab, in very-high-risk disease, inadequate control, or statin intolerance. These agents prevent extracellular PCSK9 from binding LDLR and lower LDL-C by up to approximately 60%; outcome trials totaling about 46,000 high-risk participants showed roughly 15% relative cardiovascular-risk reduction over 2.2–2.8 years. (katzmann2020pcsk9inhibitioninsights pages 1-2)
Consider inclisiran, a hepatocyte-directed siRNA suppressing PCSK9 synthesis, or bempedoic acid, particularly where adherence, injection frequency, or statin intolerance is important. A 2024 systematic review reported sustained approximately 50% LDL-C reduction with inclisiran dosed initially, at 90 days, then every six months. (rajendran2024acomparativeanalysis pages 1-2)
Lipoprotein apheresis for severe, refractory disease or progressive ASCVD despite maximal medication.

For very-high-risk FH with ASCVD, a commonly recommended goal is ≥50% LDL-C reduction and <55 mg/dL (<1.4 mmol/L). (fularski2024unveilingfamilialhypercholesterolemia—review pages 7-9)

Adverse effects and pharmacogenomics

Statins may cause myalgia and rarely myopathy/rhabdomyolysis; ezetimibe is usually well tolerated. PCSK9 antibodies chiefly cause injection-site reactions. Inclisiran also causes injection-site reactions; long-term cardiovascular outcome evidence has historically lagged its LDL-lowering evidence. Bempedoic acid may increase uric acid/gout and cholelithiasis. No validated PCSK9-GOF genotype-specific drug-dose rule exists: therapy is guided by baseline risk and achieved LDL-C.

Trials and advanced therapeutics

NCT05398029 (VERVE-101): completed phase 1, open-label, 13 adults with HeFH, ASCVD, and uncontrolled LDL-C; liver-directed base editing was designed to disrupt PCSK9. This edits a therapeutic target rather than correcting the familial GOF allele itself. (NCT05398029 chunk 1)
NCT02624869 (HAUSER-OLE): 163 participants aged 10–17; evolocumab 420 mg every four weeks for up to 80 weeks. (NCT02624869 chunk 1)
NCT04652726 (ORION-16): randomized phase 3 inclisiran study in 141 adolescents with HeFH; dosing at days 1, 90, and 270 during year 1. (NCT04652726 chunk 1)
NCT05465278 (ARCHITECT): phase 4, 104 molecularly diagnosed FH participants; alirocumab 150 mg every two weeks with coronary CT plaque assessment over 18 months. (NCT05465278 chunk 1)

A 2024 Circulation review concluded that DNA- and RNA-based therapeutics may transform FH care as formulation stability and liver-specific delivery improve, but permanent editing requires continued assessment of off-target editing, hepatic toxicity, immunogenicity, and durability. DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.067957, published August 2024. (damase2024establishedandemerging pages 1-3)

Suggested NCIt intervention concepts include statin therapy, ezetimibe, alirocumab, evolocumab, inclisiran, bempedoic acid, lipoprotein apheresis, genetic counseling, and therapeutic gene editing; exact NCIt codes should be validated against the current NCIt release.

13. Prevention

Primary prevention of genotype: not possible through lifestyle or vaccination. Genetic counseling, reproductive options, prenatal diagnosis, and preimplantation genetic testing may be discussed after identifying a familial pathogenic variant.
Secondary prevention: universal or targeted childhood lipid screening, opportunistic adult case finding, and cascade genetic/lipid screening. Each first-degree relative has a 50% prior probability.
Tertiary prevention: early, intensive, sustained LDL lowering; tobacco avoidance; treatment of hypertension/diabetes; antiplatelet and other secondary-ASCVD measures when otherwise indicated.
Public health: affordable lipid testing, FH registries, cascade-screening services, and access to statins/combination therapy. The World Heart Federation emphasizes universal screening for inherited dyslipidemias and life-course prevention because apoB/LDL exposure is cumulative. (ray2022worldheartfederation pages 1-2)
Immunization: no approved vaccine prevents ADH3. A PCSK9 nanoparticle vaccine remains experimental. (fang2024developmentofa pages 1-3)

14. Other species and natural disease

PCSK9 and LDLR biology is evolutionarily conserved across mammals. No well-established common, naturally occurring veterinary counterpart caused by spontaneous PCSK9 GOF was identified. Most nonhuman evidence is engineered rather than natural disease. Therefore, breed prevalence, zoonotic transmission, and cross-species infectious susceptibility are not applicable. ADH3 is not transmissible.

Relevant taxa are Mus musculus (NCBI Taxonomy 10090) and Sus scrofa (9823). Orthologous Pcsk9/PCSK9 regulates LDLR turnover in both species.

15. Model organisms

Mouse

A single liver-targeted AAV dose expressing human PCSK9-D374Y in wild-type mice produced sustained LDL elevation, macrophage-rich aortic lesions, and fibrous caps, especially with high-fat feeding. The model used 3.5×10¹⁰ AAV particles and avoided lengthy genetic crosses; ApoE deficiency approximately doubled lesion burden. Published January 2015, DOI: https://doi.org/10.1161/ATVBAHA.114.303617. (rochemolina2015inductionofsustained pages 1-2)

Applications include rapid atherosclerosis induction, modifier-gene testing, imaging, and therapeutic evaluation. Limitations include supraphysiologic vector expression, dietary dependence, species-specific lipoprotein metabolism, and incomplete reproduction of decades-long human disease.

Pig/minipig

Liver-specific human PCSK9-D374Y transgenic Yucatan minipigs show hepatic LDLR depletion, hypercholesterolemia, and coronary/aortic atherosclerotic lesions. Their anatomy and lipoprotein physiology make them useful for imaging and interventional translation. However, reported models did not reliably reproduce human plaque rupture or thrombosis. (perleberg2018geneticallyengineeredpigs pages 4-4, rochemolina2015inductionofsustained pages 10-10)

Recent application

A June 2024 Cell Reports Medicine study used high-fat-diet and AAV-hPCSK9-D374Y mice to test a ferritin nanoparticle PCSK9 vaccine. Vaccination reduced serum lipids, aortic plaque area, and macrophage infiltration through an LDLR- and T-follicular-helper-cell-dependent mechanism. This is preclinical evidence, not an approved preventive treatment. DOI: https://doi.org/10.1016/j.xcrm.2024.101614. (fang2024developmentofa pages 1-3)

Key direct quotations from retrieved abstracts

2023 adult guideline: “Familial hypercholesterolemia (FH) is an autosomal hereditary disorder characterized by hyperLDL cholesterolemia (LDL-C), premature coronary artery disease (CAD), and tendon and skin xanthomas.” Published May 2023; DOI: https://doi.org/10.5551/jat.CR005. (haradashiba2023guidelinesforthe pages 1-2)
2022 mechanistic study: “Gain-of-function (GOF) point mutations in PCSK9 are associated with familial hypercholesterolemia.” Published September 2022; DOI: https://doi.org/10.3389/fphys.2022.960272. (sarkar2022pathogenicgainoffunctionmutations pages 1-2)
2024 nucleic-acid review: “DNA- and RNA-based therapeutics have the potential to transform the care of patients with FH.” Published August 2024; DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.067957. (damase2024establishedandemerging pages 1-3)
2020 prevalence meta-analysis: “With an overall prevalence of 1:311, FH is among the commonest genetic disorders in the GP.” Published June 2020; DOI: https://doi.org/10.1161/CIRCULATIONAHA.119.044795. This quotation concerns all heterozygous FH, not ADH3 alone. (hu2020prevalenceoffamilial pages 1-2)

Overall assessment

The evidence establishing PCSK9 GOF as the cause of ADH3 is strong, supported by cosegregation in human pedigrees, biochemical effects on LDLR trafficking, animal phenocopy, and the clinical success of PCSK9 inhibition. The most important unresolved knowledge-base gaps are ADH3-specific prevalence, penetrance by variant, longitudinal quality-of-life data, validated molecular-omics signatures, and comparative treatment outcomes stratified specifically by PCSK9 GOF genotype.

References

(OpenTargets Search: familial hypercholesterolemia-PCSK9): Open Targets Query (familial hypercholesterolemia-PCSK9, 11 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(NCT05398029 chunk 1): A Study of VERVE-101 in Patients With Familial Hypercholesterolemia and Cardiovascular Disease. Verve Therapeutics, Inc.. 2022. ClinicalTrials.gov Identifier: NCT05398029
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Unresolved (possible confabulation)	0
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Quoted claims checked	1
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Quoted claims not found in source	0
References weighed for topical relevance	24
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Autosomal Dominant Hypercholesterolemia 3 (ADH3): Disease Characteristics Report

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2. Etiology, risk, protection, and gene–environment interaction

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4. Genetic and molecular information

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