Hypermobile Ehlers-Danlos Syndrome <-> Gastroesophageal Reflux Disease

Comorbidity UNKNOWN CANDIDATE

Gastroesophageal reflux disease (GERD) was the single most common gastrointestinal comorbidity in a large propensity-matched TriNetX cohort of EDS patients (18.4% prevalence, OR 1.5 versus matched controls), consistent with the well-documented broader pattern of GI dysmotility in hEDS (alongside constipation, IBS, and gastroparesis in the same cohort). Directionality is UNKNOWN. No ICEES KG signal exists for this pair: hEDS (MONDO:0007523) is not a node in the ICEES KG snapshot at all (confirmed while curating the hEDS-POTS comorbidity entry).

Disease A

Hypermobile Ehlers-Danlos Syndrome

Slug:Hypermobile_Ehlers-Danlos_Syndrome

Disease B

Gastroesophageal Reflux Disease

Slug:Gastroesophageal_Reflux_Disease

Causal Mechanism Graphs

Hypermobile Ehlers-Danlos Syndrome

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

Gastroesophageal Reflux Disease

graph LR
    Esophageal_Mucosal_Injury["Esophageal Mucosal Injury"]
    Na+K+_ATPase_Beta1_Gene_Therapy["Na+,K+-ATPase Beta1 Gene Therapy"]
    Alcohol_Consumption["Alcohol Consumption"]
    Tight_Junction_Protein_Loss["Tight Junction Protein Loss"]
    Dietary_Factors["Dietary Factors"]
    Lower_Esophageal_Sphincter_Dysfunction["Lower Esophageal Sphincter Dysfunction"]
    Dilated_Intercellular_Spaces["Dilated Intercellular Spaces"]

    Tight_Junction_Protein_Loss --> Dilated_Intercellular_Spaces
    Dilated_Intercellular_Spaces --> Esophageal_Mucosal_Injury
    Alcohol_Consumption --> Lower_Esophageal_Sphincter_Dysfunction
    Dietary_Factors --> Lower_Esophageal_Sphincter_Dysfunction
    Na+K+_ATPase_Beta1_Gene_Therapy --> Tight_Junction_Protein_Loss

    style Esophageal_Mucosal_Injury fill:#dbeafe
    style Na+K+_ATPase_Beta1_Gene_Therapy fill:#fce7f3
    style Alcohol_Consumption fill:#dcfce7
    style Tight_Junction_Protein_Loss fill:#dbeafe
    style Dietary_Factors fill:#dcfce7
    style Lower_Esophageal_Sphincter_Dysfunction fill:#dbeafe
    style Dilated_Intercellular_Spaces fill:#dbeafe

Association Signals

Signal 1

Population:TriNetX research network, retrospective propensity-matched analysis (2005-2023), 59,128 matched pairs of EDS patients (excluding Marfan syndrome) versus controls.

Signal IDs: MONDO:0007523 dismech -> MONDO:0007186 dismech

Temporal: A before B: , B before A: , Same time:

PREVALENCE: 18.4

CI: -

FDR:

GERD prevalence in the EDS cohort.

OR: 1.5

CI: 1.4 - 1.5

p: 0.001

FDR:

Odds ratio for GERD in EDS versus propensity-matched controls. Reported by the source as p < 0.001, an upper bound, not a point estimate.

PMID:41432355 (SUPPORT)

Source: HUMAN_CLINICAL

"Among GI disorders, gastroesophageal reflux disease was most common in EDS (18.4%, OR 1.5, 95% CI 1.4-1.5, p < 0.001)"

A large propensity-matched cohort quantifies GERD as the most common GI comorbidity in EDS patients with a statistically significant odds ratio.

Signal 2

Population:ICEES KG snapshot 8-20-2024 (RENCI/UNC).

Signal IDs: MONDO:0007523 dismech -> MONDO:0007186 dismech

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. hEDS (MONDO:0007523) does not appear among them -- confirmed by grepping the decompressed node list directly (same check performed for the hEDS-POTS comorbidity entry). No ICEES signal exists for this pair in the current snapshot; recorded here rather than silently omitted.

Temporal: A before B: , B before A: , Same time:

Hypotheses

Hypothesis: connective-tissue laxity affecting the lower esophageal sphincter and diaphragmatic crura, combined with generalized smooth muscle/visceral dysmotility and autonomic dysfunction documented across the hEDS GI tract, reduces the mechanical and neuromuscular barrier to reflux.

PMID:41432355 (SUPPORT, primary result)

Source: HUMAN_CLINICAL

"Among GI disorders, gastroesophageal reflux disease was most common in EDS (18.4%, OR 1.5, 95% CI 1.4-1.5, p < 0.001), followed by constipation (12.4%, OR 1.8, 95% CI 1.7-1.9, p < 0.001), irritable bowel syndrome (7.3%, OR 2.6, 95% CI 2.5-2.8, p < 0.001) and gastroparesis (4.7%, OR 8.2, 95% CI 7.3-9.2, p < 0.001)."

Establishes GERD as the single most prevalent GI comorbidity in EDS within a broader pattern of GI dysmotility disorders, supporting a shared connective-tissue/dysmotility mechanism.

Pathophysiology:

Esophagogastric junction laxity and visceral dysmotility: Reduced structural integrity of the lower esophageal sphincter and diaphragmatic hiatus, together with generalized GI smooth-muscle dysmotility, is proposed to lower the barrier to gastroesophageal reflux in hEDS.

Biological processes:

Raw YAML

Show YAML

name: com_Hypermobile_Ehlers-Danlos_Syndrome__Gastroesophageal_Reflux_Disease
creation_date: '2026-09-18T02:57:53Z'
curation_status: CANDIDATE
notes: >-
  Gastroesophageal reflux disease (GERD) was the single most common
  gastrointestinal comorbidity in a large propensity-matched TriNetX cohort
  of EDS patients (18.4% prevalence, OR 1.5 versus matched controls),
  consistent with the well-documented broader pattern of GI dysmotility in
  hEDS (alongside constipation, IBS, and gastroparesis in the same cohort).
  Directionality is UNKNOWN. No ICEES KG signal exists for this pair: hEDS
  (MONDO:0007523) is not a node in the ICEES KG snapshot at all (confirmed
  while curating the hEDS-POTS comorbidity entry).

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: Gastroesophageal_Reflux_Disease
  preferred_term: gastroesophageal reflux disease
  term:
    id: MONDO:0007186
    label: gastroesophageal reflux disease

directionality: UNKNOWN

hypotheses:
- description: >-
    Hypothesis: connective-tissue laxity affecting the lower esophageal
    sphincter and diaphragmatic crura, combined with generalized smooth
    muscle/visceral dysmotility and autonomic dysfunction documented across
    the hEDS GI tract, reduces the mechanical and neuromuscular barrier to
    reflux.
  evidence:
  - reference: PMID:41432355
    reference_title: "Comprehensive Risk Profile of Gastrointestinal and Extra Articular Comorbidities in Ehlers-Danlos Syndrome: A Propensity-Matched Analysis of 118,256 Individuals."
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among GI disorders, gastroesophageal reflux disease was most common in EDS (18.4%, OR 1.5, 95% CI 1.4-1.5, p < 0.001), followed by constipation (12.4%, OR 1.8, 95% CI 1.7-1.9, p < 0.001), irritable bowel syndrome (7.3%, OR 2.6, 95% CI 2.5-2.8, p < 0.001) and gastroparesis (4.7%, OR 8.2, 95% CI 7.3-9.2, p < 0.001)."
    explanation: >-
      Establishes GERD as the single most prevalent GI comorbidity in EDS
      within a broader pattern of GI dysmotility disorders, supporting a
      shared connective-tissue/dysmotility mechanism.
  pathophysiology:
  - name: Esophagogastric junction laxity and visceral dysmotility
    description: >-
      Reduced structural integrity of the lower esophageal sphincter and
      diaphragmatic hiatus, together with generalized GI smooth-muscle
      dysmotility, is proposed to lower the barrier to gastroesophageal
      reflux in hEDS.
    biological_processes:
    - preferred_term: gastro-intestinal smooth muscle dysmotility
      term:
        id: GO:0014831
        label: gastro-intestinal system smooth muscle contraction
      modifier: DECREASED

association_signals:
- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0007186
  population: >-
    TriNetX research network, retrospective propensity-matched analysis
    (2005-2023), 59,128 matched pairs of EDS patients (excluding Marfan
    syndrome) versus controls.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: PREVALENCE
      metric_value: 18.4
      notes: GERD prevalence in the EDS cohort.
    - metric_type: OR
      metric_value: 1.5
      metric_ci_lower: 1.4
      metric_ci_upper: 1.5
      p_value: 0.001
      notes: Odds ratio for GERD in EDS versus propensity-matched controls. Reported by the source as p < 0.001, an upper bound, not a point estimate.
    evidence:
    - reference: PMID:41432355
      reference_title: "Comprehensive Risk Profile of Gastrointestinal and Extra Articular Comorbidities in Ehlers-Danlos Syndrome: A Propensity-Matched Analysis of 118,256 Individuals."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Among GI disorders, gastroesophageal reflux disease was most common in EDS (18.4%, OR 1.5, 95% CI 1.4-1.5, p < 0.001)"
      explanation: >-
        A large propensity-matched cohort quantifies GERD as the most common
        GI comorbidity in EDS patients with a statistically significant odds
        ratio.

- source: ICEES
  method: EHR_COHORT_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0007186
  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. hEDS (MONDO:0007523) does not appear among them -- confirmed
    by grepping the decompressed node list directly (same check performed
    for the hEDS-POTS comorbidity entry). No ICEES signal exists for this
    pair in the current snapshot; recorded here rather than silently
    omitted.
  directionality: UNKNOWN

Source:GitHub