胆石症及胆囊切除术与胃食管反流病因果关系的相关性研究

Correlation between cholelithiasis,cholecystectomy,and gastroesophageal reflux disease

目的用孟德尔随机化(MR)研究方法探讨胆石症和胆囊切除术与胃食管反流病(GERD)的因果关系。方法基于大规模全基因组关联研究(GWAS)数据库,选择与胆石症和胆囊切除术密切相关的遗传变异作为工具变量,用MR多效性残差和异常值法(MR-PRESSO)剔除离群值,以逆方差加权法(IVW)作为主要分析方法,用MR-Egger法、加权中位数法、简单模式法和加权众数法4种统计方法作为补充进行因果效应评估。同时用Cochran’s Q进行异质性检验,用MR Egger intercept检验分析水平多效性,用留一法评估结果的稳健性。结果IVW结果显示,胆石症(比值比为1.05,95%置信区间为1.03~1.07,P<0.01)和胆囊切除术(比值比为2.56,95%置信区间为1.76~3.73,P<0.01)均与GERD风险增加显著相关。Cochran’s Q检验显示,胆石症的遗传变异存在异质性(P<0.05),胆囊切除术的遗传变异无明显异质性(P>0.05)。MR-Egger intercept分析未检测到潜在的水平多效性(P>0.05),留一法分析显示结果稳健。结论遗传学预测的胆石症和胆囊切除术与GERD存在正向因果关系,提示应加强对胆石症和胆囊切除术后患者发生GERD的预防。

Objective To use mendelian randomization(MR)study to explore the causal relationship between cholelithiasis,cholecystectomy,and gastroesophageal reflux disease(GERD).Methods Based on large-scale genome-wide association studies(GWAS),genetic variants closely associated with cholelithiasis and cholecystectomy were selected as instrumental variables.Mendelian randomization pleiotropy residual sum and outlier(MR-PRESSO)was used to eliminate outliers.Inverse variance weighting(IVW)was used as the main analysis method and MR-Egger,Weighted median,Simple mode and Weighted mode were used as supplementary analysis methods for causal effect evaluation.Meanwhile,Cochran’s Q was used for heterogeneity test.The MR Egger intercept test was used to analyze the level of horizontal pleiotropy,and the leave-one-out method was used to ensure the robustness of the results.Results Inverse variance weighted results showed that cholelithiasis(odds ratio:1.05,95%confidence interval:1.03-1.07,P<0.01)and cholecystectomy(odds ratio:2.56,95%confidence interval:1.76-3.73,P<0.01)were significantly associated with an increased risk of GERD.Cochran’s Q test showed that there was heterogeneity in the genetic variants of cholelithiasis(P<0.05),but no significant heterogeneity in the genetic variants of cholecystectomy(P>0.05).MR-Egger intercept analysis did not detect potential horizontal pleiotropy(P>0.05),and the leave-one-out analyses showed that the results were robust.Conclusion Genetically predicted cholelithiasis and cholecystectomy are causally associated with GERD,suggesting that the prevention of GERD should be strengthened in patients with cholelithiasis and after cholecystectomy.