Neurobehavioral Clinical Research Section, Social and Behavioral Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland.
Division of Pulmonary and Critical Care Medicine and.
Am J Respir Crit Care Med. 2023 Jan 15;207(2):130-137. doi: 10.1164/rccm.202205-0951OC.
Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear. We applied Mendelian randomization analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis [AD]). We conducted two-sample bidirectional Mendelian randomization to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies conducted on asthma ( = 56,167) and GERD ( = 71,522). In addition, we generated instrumental variables for AD from the latest population-level genome-wide association study meta-analysis ( = 22,474) and assessed their fidelity and confidence of predicting the likely causal pathway(s) leading to asthma and/or GERD. Applying three different methods, each method revealed similar magnitude of causal estimates that were directionally consistent across the sensitivity analyses. Using an inverse variance-weighted method, the largest effect size was detected for asthma predisposition to AD (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.34-1.59), followed by AD to asthma (OR, 1.34; 95% CI, 1.24-1.45). A significant association was detected for genetically determined asthma on risk of GERD (OR, 1.06; 95% CI, 1.03-1.09) but not genetically determined AD on GERD. In contrast, GERD equally increased risks of asthma (OR, 1.21; 95% CI, 1.09-1.35) and AD (OR, 1.21; 95% CI, 1.07-1.37). This study uncovers previously unrecognized causal pathways that have clinical implications in European-ancestry populations: ) asthma is a causal risk for AD, and ) the predisposition to AD, including asthma, can arise from specific pathogenic mechanisms manifested by GERD.
胃食管反流病(GERD)通常与特应性疾病有关,但因果关系尚不清楚。我们应用孟德尔随机化分析来探讨 GERD 是否与肺部(哮喘)和/或皮肤(特应性皮炎[AD])的特应性疾病有因果关系。我们进行了两样本双向孟德尔随机化分析,以推断哮喘和 GERD 之间因果关系的大小和方向,使用了针对哮喘( = 56167)和 GERD( = 71522)进行的最大全基因组关联研究的汇总统计数据。此外,我们从最新的人群全基因组关联研究荟萃分析中为 AD 生成了工具变量( = 22474),并评估了它们预测导致哮喘和/或 GERD 的可能因果途径的保真度和置信度。应用三种不同的方法,每种方法都揭示了因果估计值的相似大小,并且在敏感性分析中方向一致。使用逆方差加权法,检测到哮喘易患 AD 的最大效应量(比值比[OR],1.46;95%置信区间[CI],1.34-1.59),其次是 AD 易患哮喘(OR,1.34;95% CI,1.24-1.45)。在遗传决定的哮喘与 GERD 风险之间检测到显著关联(OR,1.06;95% CI,1.03-1.09),但在遗传决定的 AD 与 GERD 之间没有关联。相比之下,GERD 同样增加了哮喘(OR,1.21;95% CI,1.09-1.35)和 AD(OR,1.21;95% CI,1.07-1.37)的风险。这项研究揭示了以前未被认识到的因果途径,这些途径在欧洲血统人群中具有临床意义:)哮喘是 AD 的因果风险,)AD 的易感性,包括哮喘,可能来自 GERD 表现出的特定致病机制。
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