孟德尔随机分析揭示了特应性皮炎、哮喘和GERD之间复杂的遗传相互作用
2022/10/17
摘要
背景：胃食管反流病（GERD）常与特应性疾病相关，但因果关系尚不清楚。
目的：本研究通过孟德尔随机化（MR）分析探讨GERD是否与肺（哮喘）和/或皮肤（特应性皮炎）的特应性疾病有关。
方法：本研究采用了哮喘（N=56167）和GERD（N=71522）的最大全基因组关联研究（GWAS）的汇总统计数据，通过两个样本的双向MR来推断哮喘和GERD之间因果关系的强度和方向。此外，从最新的人群水平GWAS荟萃分析（N=22474）中我们得到特应性皮炎（AD）的工具变量（IVs），并评估了这些变量预测可能导致哮喘和/或GERD的致病途径的精确度和可信度。
结果：三种不同方法均预测出与敏感性分析方向一致的相似因果关系。通过反方差加权法，我们检测出哮喘易患AD的效应最大（比值比[OR]，1.46；95%可信区间[CI]，1.34-1.59），其次为AD易感哮喘（OR 1.34；CI 1.24-1.45）。基因决定的哮喘与GERD患病风险之间有显著相关性（OR 1.06；CI 1.03-1.09），但基因决定的AD与GERD患病风险之间无显著相关性。相比之下，GERD可同比例增加哮喘（OR，1.21；CI，1.09-1.35）和AD（OR，1.11，CI，1.07-1.37）的罹患风险。
结论：本研究揭示了以前未被认识的在欧洲血统人群中具有临床意义的致病途径：1）哮喘是AD的致病风险；2）AD（包括哮喘）的易感性可能由GERD特异性致病机制引起。
Mendelian Randomization Analysis Reveals a Complex Genetic Interplay Among Atopic Dermatitis, Asthma, and GERD.
Ahn K, Penn RB, Rattan S, Panettieri RA Jr, Voight BF, An SS.
Abstract
BACKGROUND:Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear.
OBJECTIVES: We applied Mendelian randomization (MR) analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis).
METHODS:We conducted two-sample bidirectional MR to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies (GWAS) conducted on asthma (Ncases=56,167) and GERD (Ncases=71,522). Additionally, we generated instrumental variables (IVs) for atopic dermatitis (AD) from the latest population-level GWAS meta-analysis (Ncases=22,474) and assessed their fidelity and confidence of predicting the likely causal pathway(s) leading to asthma and/or GERD.
RESULTS:Applying three different methods, each method found 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; CI, 1.24-1.45). A significant association was detected for genetically determined asthma on risk of GERD (OR, 1.06; CI, 1.03-1.09), but not genetically determined AD on GERD. In contrast, GERD equally increased risks of asthma (OR, 1.21; CI, 1.09-1.35) and AD (OR, 1.21; CI, 1.07-1.37).
CONCLUSIONS:This study uncovers previously unrecognized causal pathways that have clinical implications in European-ancestry populations: 1) asthma is a causal risk for AD; and 2) the predisposition to AD, including asthma, can arise from specific pathogenic mechanisms manifested by GERD.
背景：胃食管反流病（GERD）常与特应性疾病相关，但因果关系尚不清楚。
目的：本研究通过孟德尔随机化（MR）分析探讨GERD是否与肺（哮喘）和/或皮肤（特应性皮炎）的特应性疾病有关。
方法：本研究采用了哮喘（N=56167）和GERD（N=71522）的最大全基因组关联研究（GWAS）的汇总统计数据，通过两个样本的双向MR来推断哮喘和GERD之间因果关系的强度和方向。此外，从最新的人群水平GWAS荟萃分析（N=22474）中我们得到特应性皮炎（AD）的工具变量（IVs），并评估了这些变量预测可能导致哮喘和/或GERD的致病途径的精确度和可信度。
结果：三种不同方法均预测出与敏感性分析方向一致的相似因果关系。通过反方差加权法，我们检测出哮喘易患AD的效应最大（比值比[OR]，1.46；95%可信区间[CI]，1.34-1.59），其次为AD易感哮喘（OR 1.34；CI 1.24-1.45）。基因决定的哮喘与GERD患病风险之间有显著相关性（OR 1.06；CI 1.03-1.09），但基因决定的AD与GERD患病风险之间无显著相关性。相比之下，GERD可同比例增加哮喘（OR，1.21；CI，1.09-1.35）和AD（OR，1.11，CI，1.07-1.37）的罹患风险。
结论：本研究揭示了以前未被认识的在欧洲血统人群中具有临床意义的致病途径：1）哮喘是AD的致病风险；2）AD（包括哮喘）的易感性可能由GERD特异性致病机制引起。
(中日友好医院呼吸与危重症医学科 张婧媛 摘译 林江涛 审校)
(Am J Respir Crit Care Med. 2022 Oct 10. Epub ahead of print. doi: 10.1164/rccm.202205-0951OC.)
(Am J Respir Crit Care Med. 2022 Oct 10. Epub ahead of print. doi: 10.1164/rccm.202205-0951OC.)
Mendelian Randomization Analysis Reveals a Complex Genetic Interplay Among Atopic Dermatitis, Asthma, and GERD.
Ahn K, Penn RB, Rattan S, Panettieri RA Jr, Voight BF, An SS.
Abstract
BACKGROUND:Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear.
OBJECTIVES: We applied Mendelian randomization (MR) analysis to explore whether GERD is causally related to atopic disorders of the lung (asthma) and/or skin (atopic dermatitis).
METHODS:We conducted two-sample bidirectional MR to infer the magnitude and direction of causality between asthma and GERD, using summary statistics from the largest genome-wide association studies (GWAS) conducted on asthma (Ncases=56,167) and GERD (Ncases=71,522). Additionally, we generated instrumental variables (IVs) for atopic dermatitis (AD) from the latest population-level GWAS meta-analysis (Ncases=22,474) and assessed their fidelity and confidence of predicting the likely causal pathway(s) leading to asthma and/or GERD.
RESULTS:Applying three different methods, each method found 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; CI, 1.24-1.45). A significant association was detected for genetically determined asthma on risk of GERD (OR, 1.06; CI, 1.03-1.09), but not genetically determined AD on GERD. In contrast, GERD equally increased risks of asthma (OR, 1.21; CI, 1.09-1.35) and AD (OR, 1.21; CI, 1.07-1.37).
CONCLUSIONS:This study uncovers previously unrecognized causal pathways that have clinical implications in European-ancestry populations: 1) asthma is a causal risk for AD; and 2) the predisposition to AD, including asthma, can arise from specific pathogenic mechanisms manifested by GERD.
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重症哮喘研究计划（SARP）中的骨骼肌脂肪沉积和肺功能轨迹
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非洲人特有的等位基因改变了非洲裔美国人在17q12-q21位点上的哮喘风险
