桥本甲状腺炎与原发性胆汁性胆管炎的因果关联推论:一项两样本孟德尔随机化研究

Inference of the causal association between Hashimoto thyroiditis and primary biliary cholangitis:a two-sample Mendelian randomization study

目的 采用两样本孟德尔随机化(two-sample Mendelian randomization,TSMR)方法,探讨桥本甲状腺炎(Hashimoto thyroiditis,HT)和原发性胆汁性胆管炎(primary biliary cholangitis,PBC)之间的潜在因果关联。方法 使用IEU OpenGWAS project数据库获取不同研究来源的HT和PBC的全基因组关联研究(genome-wide association study,GWAS)数据。以HT为暴露因素、PBC为结局,选择与暴露因素显著性相关的单核苷酸多态性(single nucleotide polymorphisms,SNPs)作为工具变量(instrumental variables,IVs),采用逆方差加权法(inverse-variance weighed,IVW)作为主要分析方法,探讨HT和PBC的潜在因果关联。采用异质性检验、水平多效性检验等敏感性分析评价研究结果的稳定性和可靠性。结果 随机效应逆方差加权法(rIVW)结果显示,HT与发生PBC的风险增加相关(OR=1.853,95%CI 1.241~2.768,P=0.003),其余4种基于不同假设的MR方法结果与rIVW类似。敏感性分析显示,研究结果不受水平多效性影响,留一法检验证实了结果的稳定性。反向MR分析存在水平多效性及异质性,暂不能认为HT与PBC存在反向因果关联。结论 HT可能是PBC发生的危险因素,暂无依据支持反向因果关联。这项TSMR研究可能为进一步探讨两种疾病的发病机制提供新的见解,并为两种疾病的防治提供线索。

Objective Two-wample Mendelian randomization(TSMR)method was used to explore the potential causal association between Hashimoto thyroiditis(HT)and primary biliary cholangitis(PBC).Methods The genome-wide association study(GWAS)data of HT and PBC from different research sources were obtained through the IEU OpenGWAS project database.Taking HT as the exposure factor and PBC as the outcome,single nucleotide polymorphisms(SNPs)significantly associated with exposure factor were selected as the instrumental variables(IVs),and inverse-variance weighed(IVW)was used as the main analysis method to explore the potential causal relationship between HT and PBC.Additionally,multiple sensitivity analyses such as heterogeneity test and horizontal multiple effect test were employed to evaluate the robustness and consistency of the findings.Results The results of random-effects inverse-variance weighted(rIVW)method indicated a significant association between HT and the development of PBC(OR=1.853,95%CI 1.241-2.768,P=0.003),and the results of the other four MR methods based on different assumptions were similar to the rIVW.Sensitivity analysis showed that the results were not affected by horizontal pleiotropy,and the robustness of the results was confirmed by leaving-one test.Reverse MR analysis,due to the presence of horizontal pleiotropy and failure to meet the criteria of the MR Egger test,could not establish a reverse causality of PBC on HT.Conclusions HT may be a risk factor for the occurrence of PBC,and there is no evidence to support reverse causality.This may potentially offer novel insights into the pathogenesis of both diseases,thereby providing avenues for further research,as well as clues for the prevention and treatment of these two conditions.