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孟德尔随机化分析揭示特应性皮炎、哮喘和胃食管反流病之间复杂的遗传相互作用。

Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease.

机构信息

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.

出版信息

Am J Respir Crit Care Med. 2023 Jan 15;207(2):130-137. doi: 10.1164/rccm.202205-0951OC.


DOI:10.1164/rccm.202205-0951OC
PMID:36214830
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9893317/
Abstract

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.

摘要

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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本文引用的文献

[1]
Revisiting the Atopic March Current Evidence.

Am J Respir Crit Care Med. 2022-10-15

[2]
Robust inference of bi-directional causal relationships in presence of correlated pleiotropy with GWAS summary data.

PLoS Genet. 2022-5-16

[3]
Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach.

Nat Commun. 2022-4-28

[4]
Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension.

Am J Respir Crit Care Med. 2022-6-15

[5]
Asthma and the risk of gastrointestinal disorders: a Mendelian randomization study.

BMC Med. 2022-3-16

[6]
Harnessing tissue-specific genetic variation to dissect putative causal pathways between body mass index and cardiometabolic phenotypes.

Am J Hum Genet. 2022-2-3

[7]
Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies.

BMC Med. 2021-12-15

[8]
Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes.

Am J Respir Crit Care Med. 2022-1-1

[9]
Association of Treated and Untreated Gastroesophageal Reflux Disease in the First Year of Life with the Subsequent Development of Asthma.

Int J Environ Res Public Health. 2021-9-13

[10]
Uniting biobank resources reveals novel genetic pathways modulating susceptibility for atopic dermatitis.

J Allergy Clin Immunol. 2022-3

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