R.H. Maclean, BMBCh, F. Ahmed, MBBS, V.H. Ong, PhD, C.P. Denton, PhD, Centre for Rheumatology, Royal Free Campus, Division of Medicine, University College London.
C.D. Murray, PhD, Department of Gastroenterology, Royal Free London, London, UK.
J Rheumatol. 2023 Jul;50(7):907-915. doi: 10.3899/jrheum.220990. Epub 2023 Feb 15.
To explore the causes of and contributors to gastrointestinal (GI) dysfunction in systemic sclerosis (SSc) in a phenome-wide association study (PheWAS), using real-world clinical records data.
Twelve thousand five hundred thirty-five documented clinical assessments of 2058 consenting individuals with SSc 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 6 important SSc-GI domains (constipation, diarrhea, dysmotility, incontinence, gastroesophageal reflux, and small intestinal bacterial overgrowth [SIBO]) and exposure to various comorbidities and drugs. "Hits" from the PheWAS model were confirmed and explored in a subcohort reporting quantitative GI symptom scores from the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (GIT 2.0) questionnaire.
One thousand five hundred forty-six individuals were entered into the PheWAS analysis. Six hundred seventy-three 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 6 important SSc-GI outcomes: constipation, diarrhea, dysmotility, incontinence, reflux, and SIBO. Subsequently, using GIT 2.0 symptom scores links with SSc-GI were confirmed for 22 drugs, 4 diagnoses, and 3 ANAs.
Using a hypothesis-free PheWAS approach, we replicated known, and revealed potential novel, risk factors for SSc-GI dysfunction, including drug classes such as opioid, antimuscarinic, and endothelin receptor antagonist, and ANA subgroup.
通过表型全基因组关联研究（PheWAS），利用真实世界的临床记录数据，探讨系统性硬化症（SSc）患者胃肠道（GI）功能障碍的病因和影响因素。
在英国皇家自由医院（Royal Free Hospital），对 2058 名同意参与研究的 SSc 患者的 12535 份详细临床评估记录进行了分析。诊断和药物分别与结构化术语词典（疾病本体论项目和 DrugBank 开放数据）进行了映射。使用 PheWAS 模型来探索 6 个重要的 SSc-GI 领域（便秘、腹泻、动力障碍、失禁、胃食管反流和小肠细菌过度生长[ SIBO ]）与各种合并症和药物暴露之间的联系。从 PheWAS 模型中获得的“命中”结果在一个亚队列中得到了证实和探索，该亚队列报告了来自加利福尼亚大学洛杉矶分校硬皮病临床试验联盟胃肠道工具 2.0（GIT 2.0）问卷的定量 GI 症状评分。
在 PheWAS 分析中，共有 1546 人纳入分析。在数据集中共确定了 673 种不同的诊断和 634 种不同的药物，以及 SSc 特异性表型，如抗核抗体（ANA）。PheWAS 分析显示，药物、诊断和 ANA 与 6 个重要的 SSc-GI 结果之间存在关联：便秘、腹泻、动力障碍、失禁、反流和 SIBO。随后，使用 GIT 2.0 症状评分，与 SSc-GI 的关联在 22 种药物、4 种诊断和 3 种 ANA 中得到了确认。
通过一种无假设的 PheWAS 方法，我们复制了已知的、并揭示了 SSc-GI 功能障碍的潜在新风险因素，包括阿片类药物、抗毒蕈碱药物和内皮素受体拮抗剂等药物类别，以及 ANA 亚群。
