两样本孟德尔随机化分析哮喘与慢性阻塞性肺疾病的因果关系

The causal relationship between asthma and chronic obstructive pulmonary disease based on a two-sample Mendelian randomization analysis

目的:采用两样本孟德尔随机化(mendelian randomization,MR)方法探究哮喘和慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)间是否存在因果关系。方法:从全基因组关联研究(genome-wide association studies,GWAS)汇总数据中筛选出与哮喘强相关的单核苷酸多态性(single nucleotide polymorphism,SNP)作为工具变量,采用逆方差加权法(inverse variance weighted,IVW)作为主要分析方法,MR-Egger法、加权中位数法、简单模型和加权模型作为辅助分析方法,以评价哮喘和COPD发病风险之间的因果关系,同时采用孟德尔随机多态性残差和离群值(mendelian randomization pleiotropy residual sum and outlier,MR-PRESSO)检验检测是否存在离群的SNP,MR-Egger截距测试、Cochran Q检验评估工具变量的水平多效性和异质性。结果:共纳入61个SNP,IVW结果显示,哮喘是COPD的危险因素(OR=1.146,95%CI=1.023-1.283,P=0.020;OR=1.153,95%CI=1.003~1.326,P=0.045),其余4种辅助分析方法的结果与IVW方法显示的结果一致,MR-PRESSO检验、Cochran Q检验、MR-Egger截距测试以及留一法的结果均显示了结果的稳定性。结论:哮喘是COPD的危险因素。

Objective:To investigate whether there is a causal relationship between asthma and chronic obstructive pulmonary disease(COPD)using the two-sample Mendelian randomization(MR)approach.Methods:Single nucleotide polymorphisms(SNPs)strongly associated with asthma were obtained as instrumental variables(IVs)from the pooled data of genome-wide association studies,and the inverse variance weighted(IVW)method was used as the main analytical method,assisted by the methods of MR-Egger,weighted median,simple model,and weighted model,to evaluate the causal relationship between asthma and the risk of COPD.At the same time,the MR-PRESSO test was used to detect whether there was an outlier SNP,and the MR-Egger intercept test and the Cochran Q test were used to evaluate the horizontal pleiotropy and heterogeneity of IVs.Results:A total of 61 SNPs were included,and IVW results showed that asthma is a risk factor for COPD.(odds ratio[OR]=1.146,95%CI=1.023-1.283,P=0.020;OR=1.153,95%CI=1.003-1.326,P=0.045),and the results of the other four auxiliary analysis methods were consistent with the results of IVW.The results of the MR-PRESSO test,the Cochran Q test,the MR-Egger intercept test,and the leave-one-out method all showed the stability of the above results.Conclusion:Asthma may increase the risk of COPD.