A Phenome-Wide Association Study of Drugs and Comorbidities Associated With Gastrointestinal Dysfunction in Systemic Sclerosis

Abstract

ObjectiveTo explore the causes of and contributors to gastrointestinal (GI) dysfunction in systemic sclerosis in a Phenome-Wide Association Study (PheWAS), using real-world clinical records data.Methods12,535 documented clinical assessments of 2,058 consented individuals with systemic sclerosis at the Royal Free Hospital (UK) were available for detailed phenotyping. Diagnoses and drugs were mapped to structured dictionaries of terms (Disease Ontology project and DrugBank Open Data, respectively). A PheWAS model was used to explore links between six important SSc-GI domains (constipation, diarrhoea, dysmotility, incontinence, reflux, and SIBO) and exposure to various comorbidities and drugs. 'Hits' from the PheWAS model were confirmed and explored in a sub-cohort reporting quantitative GI symptom scores from the UCLA GIT 2.0 questionnaire (GIT 2.0).Results1,546 individuals were entered into the PheWAS analysis. 673 distinct diagnoses and 634 distinct drugs were identified in the dataset, as well as SSc-specific phenotypes such as antinuclear antibodies (ANA). PheWAS analysis revealed associations between drugs, diagnoses, and ANAs with six important SSc-GI outcomes: constipation, diarrhoea, dysmotility, incontinence, reflux, and SIBO. Subsequently, using GIT 2.0 symptom scores, links with SSc-GI were confirmed for 22 drugs, four diagnoses, and three ANAs.ConclusionUsing a hypothesis-free PheWAS approach, we replicated known, and revealed potential novel, risk factors for SSc-GI dysfunction, including drug classes such as opioid, anti-muscarinic, and endothelin receptor antagonist, and ANA subgroup.

Risk of Malnutrition in Patients With Systemic Sclerosis‐Associated Interstitial Lung Disease Treated With Nintedanib in the Randomized, Placebo‐Controlled SENSCIS Trial

“…There is some evidence to suggest that the risks of various types of gastrointestinal involvement, and their severity, vary between patients with SSc with different characteristics related to sex (24,25), autoantibody profile (25)(26)(27)(28)(29), duration of SSc (25,27), SSc subtype (dcSSc versus limited cutaneous SSc) (25,29), manifestations of SSc such as myopathy (24,25), and medication use (29,30). A number of factors have been associated with malnutrition in patients with SSc, such as a greater number of gastrointestinal symptoms (6), the presence of oral aperture or microstomia (6,31), and greater disease severity (6,7,9).…”

Identification of Novel Genes Associated with Atrial Fibrillation and Development of Atrial Fibrillation Predictive Models by Incorporating Polygenic Risk Scores and PheWAS-Derived Risk Factors

“…Therefore, integrating PheWAS-derived risk factors into the predictive models for a particular disease can further enhance the accuracy and clinical utility by capturing a broader spectrum of risk factors beyond genetics alone. 12 However, there is no large sample size report of PheWAS for AF currently.…”