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
2023/02/20
摘要
背景：胃食管反流病 (GERD) 通常与特应性疾病有关，但因果关系仍不清楚。
目的：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。
方法：我们使用对哮喘 (N = 56,167) 和 GERD (N = 71,522) 进行的最大全基因组关联研究的汇总统计数据，进行了双样本双向孟德尔随机化，以推断哮喘和 GERD 之间因果关系的大小和方向。此外，我们从最新的人群水平全基因组关联研究荟萃分析 (N = 22,474) 中生成了 AD 的工具变量，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.
结果：应用三种不同的方法，每种方法都揭示了在整个敏感性分析中方向一致的因果估计的相似幅度。使用逆方差加权法，检测到哮喘AD易感性的最大效应量（比值比 [OR]，1.46；95% 置信区间 [CI]，1.34-1.59），次于 AD 哮喘易感性（OR，1.34；95%置信区间，1.24-1.45）。遗传决定的哮喘与 GERD 风险显着相关（OR，1.06；95% CI，1.03-1.09），但遗传决定的AD与GERD 没有显着关联。相比之下，GERD 同样会增加哮喘（OR，1.21；95% CI，1.09-1.35）和 AD（OR，1.21；95% CI，1.07-1.37）的风险。
结论：这项研究揭示了以前未被识别的在欧洲血统人群中具有临床意义的因果途径：1）哮喘是AD的因果风险，2）AD的易感性，包括哮喘，可能由GERD表现出的特定致病机制引起。
Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease
Ahn K, Penn RB, Rattan S
Abstrast
Background: Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear.
Objective: 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]).
Methods: 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 (N = 56,167) and GERD (N = 71,522). In addition, we generated instrumental variables for AD from the latest population-level genome-wide association study meta-analysis (N = 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 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).
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) 通常与特应性疾病有关，但因果关系仍不清楚。
目的：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。
方法：我们使用对哮喘 (N = 56,167) 和 GERD (N = 71,522) 进行的最大全基因组关联研究的汇总统计数据，进行了双样本双向孟德尔随机化，以推断哮喘和 GERD 之间因果关系的大小和方向。此外，我们从最新的人群水平全基因组关联研究荟萃分析 (N = 22,474) 中生成了 AD 的工具变量，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.
结果：应用三种不同的方法，每种方法都揭示了在整个敏感性分析中方向一致的因果估计的相似幅度。使用逆方差加权法，检测到哮喘AD易感性的最大效应量（比值比 [OR]，1.46；95% 置信区间 [CI]，1.34-1.59），次于 AD 哮喘易感性（OR，1.34；95%置信区间，1.24-1.45）。遗传决定的哮喘与 GERD 风险显着相关（OR，1.06；95% CI，1.03-1.09），但遗传决定的AD与GERD 没有显着关联。相比之下，GERD 同样会增加哮喘（OR，1.21；95% CI，1.09-1.35）和 AD（OR，1.21；95% CI，1.07-1.37）的风险。
结论：这项研究揭示了以前未被识别的在欧洲血统人群中具有临床意义的因果途径：1）哮喘是AD的因果风险，2）AD的易感性，包括哮喘，可能由GERD表现出的特定致病机制引起。
(中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校)
(Am J Respir Crit Care Med 2023 Jan 15;207(2) doi:10.1164/rccm.202205-0951OC IF: 17.452)
(Am J Respir Crit Care Med 2023 Jan 15;207(2) doi:10.1164/rccm.202205-0951OC IF: 17.452)
Mendelian Randomization Analysis Reveals a Complex Genetic Interplay among Atopic Dermatitis, Asthma, and Gastroesophageal Reflux Disease
Ahn K, Penn RB, Rattan S
Abstrast
Background: Gastroesophageal reflux disease (GERD) is commonly associated with atopic disorders, but cause-effect relationships remain unclear.
Objective: 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]).
Methods: 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 (N = 56,167) and GERD (N = 71,522). In addition, we generated instrumental variables for AD from the latest population-level genome-wide association study meta-analysis (N = 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 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).
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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罗氟司特用于治疗肥胖患者控制不佳的哮喘时，可能会增加病情加重的风险
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痰液2型标志物可预测抗白细胞介素-5治疗的重症哮喘的缓解
