DataSheet_1_Causal relationship between eosinophilic esophagitis and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study.docx

BackgroundEosinophilic esophagitis (EoE) and inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are immune-mediated gastrointestinal diseases with overlapped pathogenesis and are sometimes concurrently diagnosed, but their causal relationship remains unclear. We investigated the causal relationship between EoE and IBD and its subtypes via a two-sample bidirectional Mendelian randomization (MR) approach.
MethodsMR analyses were performed using summary data of a genome-wide association study (GWAS) on individuals of European ancestry. Independent single-nucleotide polymorphisms correlated with EoE (from a GWAS meta-analysis containing 1,930 cases and 13,634 controls) and IBD (from FinnGen GWASs containing 9,083 IBD, 2,033 CD, and 5,931 UC cases, and GWASs of IBD genetic consortium containing 12,882 IBD, 6,968 UC, and 5,956 CD cases) were selected as instruments. We applied the inverse variance weighted (IVW) method as the primary analysis followed by several sensitivity analyses. For the forward MR study, estimates from IVW methods were subsequently meta-analyzed using a random-effect model.
ResultsOur results suggested a causal effect of EoE on IBD [pooled odds ratio (OR), 1.07; 95% confidence interval (CI), 1.02–1.13] and EoE on UC (pooled OR, 1.09, 95% CI, 1.04–1.14). No causal link between EoE and CD was observed (pooled OR, 1.05; 95% CI, 0.96–1.16). The reverse MR analyses revealed no causal effect of IBD (and its subtypes) on EoE. Sensitivity analyses confirmed the robustness of primary results.
ConclusionsOur findings provided evidence of a suggestive causal effect of EoE on IBD (specifically on UC) in the European population. Increased awareness of concurrent or subsequent IBD in patients with EoE is called for. Still, the present evidence is not adequate enough and ought to be validated by further investigations.

背景
嗜酸性食管炎（Eosinophilic esophagitis, EoE）与包括克罗恩病（Crohn’s disease, CD）、溃疡性结肠炎（Ulcerative colitis, UC）在内的炎症性肠病（inflammatory bowel diseases, IBDs）均为免疫介导的胃肠道疾病，二者发病机制存在重叠，有时会被同时诊断，但二者的因果关联仍不明确。本研究采用双样本双向孟德尔随机化（two-sample bidirectional Mendelian randomization, MR）方法，探究EoE与IBD及其亚型之间的因果关系。

方法
孟德尔随机化分析使用了欧洲血统人群的全基因组关联研究（genome-wide association study, GWAS）汇总数据。研究选取与EoE相关的独立单核苷酸多态性（single-nucleotide polymorphisms, SNPs）——数据来自一项包含1930例病例与13634例对照的GWAS荟萃分析——以及与IBD相关的独立单核苷酸多态性：IBD相关数据来自FinnGen GWAS数据库（包含9083例IBD、2033例CD与5931例UC病例）以及IBD遗传联盟GWAS数据库（包含12882例IBD、6968例UC与5956例CD病例），将其作为工具变量。本研究以逆方差加权（inverse variance weighted, IVW）法作为主要分析方法，随后开展多项敏感性分析。对于正向孟德尔随机化研究，采用随机效应模型对逆方差加权法的估计结果进行荟萃分析。

结果
本研究结果显示，EoE对IBD存在因果效应[合并比值比（pooled odds ratio, OR）=1.07；95%置信区间（confidence interval, CI）：1.02~1.13]，且EoE对UC存在因果效应（合并OR=1.09，95%CI：1.04~1.14）；未观察到EoE与CD之间存在因果关联（合并OR=1.05；95%CI：0.96~1.16）。反向孟德尔随机化分析显示，IBD及其亚型对EoE均无因果效应。敏感性分析证实了主要分析结果的稳健性。

结论
本研究结果为欧洲人群中EoE对IBD（尤其是UC）存在潜在因果效应提供了证据。临床中应加强对EoE患者并发或继发IBD的关注。不过当前证据仍存在局限性，有待后续研究进一步验证。