graph LR
Joint_instability_and_recurrent_soft_tissue_injury["Joint instability and recurrent soft-tissue injury"]
Joint_dislocation["Joint dislocation"]
Candidate_extracellular_matrix_remodeling_abnormalities["Candidate extracellular matrix remodeling abnormalities"]
Sleep_disturbance["Sleep disturbance"]
Chronic_pain["Chronic pain"]
Arthralgia["Arthralgia"]
Joint_hypermobility["Joint hypermobility"]
Myofibroblast_like_fibroblast_transition["Myofibroblast-like fibroblast transition"]
Candidate_extracellular_matrix_remodeling_abnormalities --> Myofibroblast_like_fibroblast_transition
Joint_instability_and_recurrent_soft_tissue_injury --> Joint_dislocation
Joint_instability_and_recurrent_soft_tissue_injury --> Chronic_pain
Joint_instability_and_recurrent_soft_tissue_injury --> Arthralgia
Joint_hypermobility --> Joint_instability_and_recurrent_soft_tissue_injury
Chronic_pain --> Sleep_disturbance
style Joint_instability_and_recurrent_soft_tissue_injury fill:#dbeafe
style Joint_dislocation fill:#fef3c7
style Candidate_extracellular_matrix_remodeling_abnormalities fill:#dbeafe
style Sleep_disturbance fill:#fef3c7
style Chronic_pain fill:#fef3c7
style Arthralgia fill:#fef3c7
style Joint_hypermobility fill:#fef3c7
style Myofibroblast_like_fibroblast_transition fill:#dbeafe
graph LR
Occupational_Exposures["Occupational Exposures"]
Air_Pollution["Air Pollution"]
Anxiety["Anxiety"]
Airway_Inflammation["Airway Inflammation"]
Cyanosis["Cyanosis"]
ADAM33["ADAM33"]
STAT3["STAT3"]
Respiratory_Distress["Respiratory Distress"]
Mucus_Overproduction["Mucus Overproduction"]
Reduced_Exercise_Tolerance["Reduced Exercise Tolerance"]
Blood_Eosinophil_Count_BEC["Blood Eosinophil Count (BEC)"]
Prenatal_Acid_Suppressive_Medication_Exposure["Prenatal Acid-Suppressive Medication Exposure"]
Fatigue["Fatigue"]
Wheezing["Wheezing"]
Exercise_Intolerance["Exercise Intolerance"]
Bronchoconstriction["Bronchoconstriction"]
Tobacco_Smoke["Tobacco Smoke"]
CDHR3["CDHR3"]
House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling["House Dust Mite Allergen Protease-Induced Epithelial Oxidant Signaling"]
Type_2_Immune_Response___Th2_Signaling["Type 2 Immune Response / Th2 Signaling"]
Allergens["Allergens"]
Coughing["Coughing"]
Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception["Early-Life Rhinovirus Wheezing Illness and Asthma Inception"]
IL13["IL13"]
Rapid_Breathing["Rapid Breathing"]
Chest_Tightness["Chest Tightness"]
STAT6_Degrader_SAR448272_NX_3911["STAT6 Degrader (SAR448272/NX-3911)"]
IL4["IL4"]
Airway_Remodeling["Airway Remodeling"]
Sleep_Disturbance["Sleep Disturbance"]
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation["SIRT1-Mediated NAD+ Signaling and Protective Deacetylation"]
Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling["Hill mechanochemical morphoelastic model of asthmatic airway remodelling"]
Winkler_integrative_bronchial_tree_model_of_asthmatic_bronchoconstriction["Winkler integrative bronchial-tree model of asthmatic bronchoconstriction"]
Airway_Inflammation --> Bronchoconstriction
Type_2_Immune_Response___Th2_Signaling --> Airway_Inflammation
Type_2_Immune_Response___Th2_Signaling --> Mucus_Overproduction
Bronchoconstriction --> Wheezing
Bronchoconstriction --> Chest_Tightness
Bronchoconstriction --> Rapid_Breathing
Bronchoconstriction --> Respiratory_Distress
Bronchoconstriction --> Cyanosis
Bronchoconstriction --> Exercise_Intolerance
Bronchoconstriction --> Reduced_Exercise_Tolerance
Bronchoconstriction --> Fatigue
Bronchoconstriction --> Anxiety
Mucus_Overproduction --> Coughing
Mucus_Overproduction --> Sleep_Disturbance
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Type_2_Immune_Response___Th2_Signaling
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Mucus_Overproduction
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Airway_Remodeling
SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation --> Bronchoconstriction
Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception --> Type_2_Immune_Response___Th2_Signaling
House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling --> Airway_Inflammation
Wheezing --> Respiratory_Distress
Wheezing --> Reduced_Exercise_Tolerance
Allergens --> Type_2_Immune_Response___Th2_Signaling
Air_Pollution --> Airway_Inflammation
Tobacco_Smoke --> Airway_Inflammation
Occupational_Exposures --> Airway_Inflammation
Prenatal_Acid_Suppressive_Medication_Exposure --> Type_2_Immune_Response___Th2_Signaling
STAT6_Degrader_SAR448272_NX_3911 --> Type_2_Immune_Response___Th2_Signaling
Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling --> Airway_Remodeling
Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling --> Bronchoconstriction
Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling --> Airway_Inflammation
Winkler_integrative_bronchial_tree_model_of_asthmatic_bronchoconstriction --> Bronchoconstriction
Type_2_Immune_Response___Th2_Signaling -.-> Blood_Eosinophil_Count_BEC
IL4 --> Type_2_Immune_Response___Th2_Signaling
IL13 --> Type_2_Immune_Response___Th2_Signaling
ADAM33 --> Airway_Remodeling
STAT3 --> SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation
CDHR3 --> Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception
style Occupational_Exposures fill:#dcfce7
style Air_Pollution fill:#dcfce7
style Anxiety fill:#fef3c7
style Airway_Inflammation fill:#dbeafe
style Cyanosis fill:#fef3c7
style ADAM33 fill:#f3e8ff
style STAT3 fill:#f3e8ff
style Respiratory_Distress fill:#fef3c7
style Mucus_Overproduction fill:#dbeafe
style Reduced_Exercise_Tolerance fill:#fef3c7
style Blood_Eosinophil_Count_BEC fill:#e0e7ff
style Prenatal_Acid_Suppressive_Medication_Exposure fill:#dcfce7
style Fatigue fill:#fef3c7
style Wheezing fill:#fef3c7
style Exercise_Intolerance fill:#fef3c7
style Bronchoconstriction fill:#dbeafe
style Tobacco_Smoke fill:#dcfce7
style CDHR3 fill:#f3e8ff
style House_Dust_Mite_Allergen_Protease_Induced_Epithelial_Oxidant_Signaling fill:#dbeafe
style Type_2_Immune_Response___Th2_Signaling fill:#dbeafe
style Allergens fill:#dcfce7
style Coughing fill:#fef3c7
style Early_Life_Rhinovirus_Wheezing_Illness_and_Asthma_Inception fill:#dbeafe
style IL13 fill:#f3e8ff
style Rapid_Breathing fill:#fef3c7
style Chest_Tightness fill:#fef3c7
style STAT6_Degrader_SAR448272_NX_3911 fill:#fce7f3
style IL4 fill:#f3e8ff
style Airway_Remodeling fill:#dbeafe
style Sleep_Disturbance fill:#fef3c7
style SIRT1_Mediated_NAD+_Signaling_and_Protective_Deacetylation fill:#dbeafe
style Hill_mechanochemical_morphoelastic_model_of_asthmatic_airway_remodelling fill:#ecfccb
style Winkler_integrative_bronchial_tree_model_of_asthmatic_bronchoconstriction fill:#ecfccb
name: com_Hypermobile_Ehlers-Danlos_Syndrome__Asthma
creation_date: '2026-09-18T02:57:53Z'
curation_status: CANDIDATE
notes: >-
A 2021 review of respiratory manifestations in EDS/HSD reports that asthma
(diagnosed by symptoms and variable airflow obstruction) was observed in
23% of a cohort of 43 EDS patients (mainly classical EDS) and 37% of 51
joint hypermobility syndrome (JHS) patients, compared to 14% of controls,
alongside increased serum IgE in a quarter of the EDS group and a fifth of
the JHS group -- an atopic pattern the review's authors note may reflect
overlapping polygenic risk between asthma and EDS/hypermobility rather
than a purely mechanical airway effect. The cited primary cohort was
mainly classical EDS rather than hEDS specifically, but is combined with a
JHS cohort that overlaps substantially with current hEDS/HSD
classification; recorded against hEDS as the numerically dominant
EDS/hypermobility-spectrum phenotype. Directionality is UNKNOWN. No ICEES
KG signal exists for this specific hEDS-asthma pair despite the ICEES KG
snapshot itself being built around an asthma cohort (see association_signals).
disease_a:
slug: Hypermobile_Ehlers-Danlos_Syndrome
preferred_term: Ehlers-Danlos syndrome, hypermobility type
term:
id: MONDO:0007523
label: Ehlers-Danlos syndrome, hypermobility type
disease_b:
slug: Asthma
preferred_term: asthma
term:
id: MONDO:0004979
label: asthma
directionality: UNKNOWN
hypotheses:
- description: >-
Hypothesis: EDS/hypermobility and asthma may share overlapping
polygenic risk (asthma being itself a polygenic disease), with the
airway/atopic phenotype further modified by connective-tissue-related
changes in airway and lung-parenchyma mechanical properties (increased
distensibility, propensity to airway collapse) documented elsewhere in
the same EDS respiratory literature, rather than asthma in hEDS being a
purely mechanical airway phenomenon.
evidence:
- reference: PMID:34291699
reference_title: "A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "It has been proposed that asthma, which is a polygenic disease, may have overlapping genes with EDS, with the phenotype modified by genetic and environmental factors."
explanation: >-
States the shared-polygenic-risk hypothesis for the EDS/hypermobility
and asthma association, as distinct from a purely mechanical
explanation.
pathophysiology:
- name: Atopic and airway-mechanical predisposition
description: >-
Proposed convergence of shared polygenic atopic/asthma risk with
connective-tissue-related changes in airway and lung-parenchyma
mechanics, contributing to increased asthma prevalence in EDS and
hypermobility spectrum disorders.
biological_processes:
- preferred_term: airway smooth muscle contraction
term:
id: GO:0006939
label: smooth muscle contraction
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
signal_disorder_a_id: MONDO:0007523
signal_disorder_b_id: MONDO:0004979
population: >-
Cohort of 43 EDS patients (mainly classical EDS) and 51 joint
hypermobility syndrome (JHS) patients, compared against control
subjects; cited within a 2021 review of EDS/HSD respiratory
manifestations.
mapping_notes: >-
The primary cohort is mainly classical EDS combined with a separately
reported JHS group, not a hEDS-specific cohort under current
nomenclature; JHS substantially overlaps with current hEDS/HSD
classification. Recorded against hEDS as the numerically dominant
EDS/hypermobility-spectrum phenotype.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 23.0
notes: Asthma prevalence in the EDS subgroup (mainly classical EDS, n=43).
- metric_type: PREVALENCE
metric_value: 37.0
notes: Asthma prevalence in the JHS subgroup (n=51).
- metric_type: PREVALENCE
metric_value: 14.0
notes: Asthma prevalence in controls.
evidence:
- reference: PMID:34291699
reference_title: "A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders."
supports: SUPPORT
quote_role: REVIEW_SYNTHESIS
evidence_source: HUMAN_CLINICAL
snippet: "asthma was observed in 23% of 43 EDS patients (mainly classical EDS) and 37% of 51 JHS patients compared to 14% of controls"
explanation: >-
Directly quantifies increased asthma prevalence in EDS and JHS
cohorts relative to controls.
- source: ICEES
method: EHR_COHORT_ASSOCIATION
signal_disorder_a_id: MONDO:0007523
signal_disorder_b_id: MONDO:0004979
population: ICEES KG snapshot 8-20-2024 (RENCI/UNC).
mapping_notes: >-
Searched: the local ICEES KG snapshot (rebuilt with `just icees-refresh`)
contains only 226 nodes total, a small set of UNC-Health cohort-specific
concepts (including asthma, since one ICEES cohort is asthma-specific).
hEDS (MONDO:0007523) does not appear among the 226 nodes at all --
confirmed by grepping the decompressed node list directly (same check
performed for the hEDS-POTS comorbidity entry) -- so no asthma-hEDS pair
signal can be built despite asthma itself being represented in the
snapshot. Recorded here rather than silently omitted.
directionality: UNKNOWN