孟德尔随机化分析胆石症与原发性硬化性胆管炎因果关系研究

Mendelian randomization unveils causal relationship between cholelithiasis and primary sclerosing cholangitis

目的探索胆石症与原发性硬化性胆管炎(PSC)之间的因果关系。方法PSC的汇总数据来自国际PSC遗传学研究组(IPSCSG)开展的PSC全基因组关联研究和芬兰生物银行最新(FinnGen R10)的PSC汇总数据,开展孟德尔随机化(MR)分析,首先提取和胆石症密切相关的遗传工具变量,然后采用逆方差加权(IVW)和中位数加权(WM)法估算胆石症与PSC的因果关系,最后再应用反向MR评估PSC是否能导致胆石症。结果正向MR分析发现,胆石症能升高PSC的发生风险(OR_(IVW):1.379,95%CI:1.052~1.807,P=0.020;OR WM:1.450,95%CI:1.014~2.074,P=0.042),并且该结论在芬兰生物银行中得到证实(OR_(IVW):1.98995,%CI:1.517~2.610,P=6.76×10^(-7);OR WM:1.931,95%CI:1.302~2.865,P=0.001);反向MR研究发现PSC并不改变胆石症的发病风险(OR_(IVW):1.008,95%CI:0.991~1.024,P=0.356)。结论经MR研究发现胆石症是PSC发生的重要风险因素,而反向因果关系不成立。

Objective The aim of this study was to explore causal relationship between cholelithiasis and primary sclerosing cholangitis(PSC).Methods Materials of patients with PSC were retrieved from International PSC Genetics Research Group(IPSCSG)and Finnish Biobank(FinnGen R10),and Mendelian randomization(MR)analysis was conducted by integrating summary data of published genome-wide association studies.Genetic instruments closely associated with cholelithiasis were extracted,and then causal relationship between cholelithiasis and PSC was estimated by using inverse-variance weighted(IVW)and weighted median(WM)methods.Finally,reverse MR was applied to assess whether PSC could lead to altered risk of cholelithiasis.Results Forward MR analysis found that genetic susceptibility to cholelithiasis could increase the risk of PSC(OR_(IVW):1.379,95%CI:1.052-1.807,P=0.020;OR WM:1.450,95%CI:1.014-2.074,P=0.042),and this result was validated in the FinnGen(OR_(IVW):1.989,95%CI:1.517-2.610,P=6.76×10^(-7);OR WM:1.931,95%CI:1.302-2.865,P=0.001);reverse MR analysis found that genetically-predicted PSC did not alter the risk of cholelithiasis(OR_(IVW):1.008,95%CI:0.991-1.024,P=0.356).Conclusion This MR study find cholelithiasis is an important risk factor for occurrence of PSC,and the reverse causality is not established.