代谢紊乱与原发性胆汁性胆管炎的因果关系：基于双向双样本孟德尔随机化分析

Causal relationship between metabolic disorder and primary biliary cholangitis: a bidirectional two-sample Mendelian randomization analysis

摘要

目的 采用双向两样本孟德尔随机化（MR）探讨代谢紊乱与原发性胆汁性胆管炎的因果关系。方法 基于全基因组关联研究数据库选取代谢紊乱数据集和原发性胆汁性胆管炎数据集。以逆方差加权法（IVW）、MR-Egger回归、简单模式、加权模式、加权中位数法、最大似然比法分析两者之间是否存在因果关联。采用Cochran's Q检验单核苷酸多态性（SNP）的异质性，MR Egger回归截距分析SNP水平多效性。为确保结果稳健，采用留一法分析敏感性。采用MR-多效性残差和离群值检测（PRESSO）所纳SNP是否有离群值。结果 最终纳入8个与代谢紊乱高度相关的SNP，39个与原发性胆汁性胆管炎紧密关联的SNP。在正向MR分析中，以代谢紊乱作为暴露因素，IVW结果显示，代谢紊乱会增加原发性胆汁性胆管炎的发病风险（OR=1.258，95% CI：[1.016，1.559]， P<0.05），表明代谢紊乱会增加原发性胆汁性胆管炎的发病风险。而在反向MR分析中，当暴露因素为原发性胆汁性胆管炎时，IVW结果显示，其可增加代谢紊乱的风险（OR=1.022，95% CI：[1.003，1.041]， P<0.05），说明其可增加代谢紊乱的风险。Cochran's Q检验显示，与代谢紊乱或原发性胆汁性胆管炎相关的SNP，均未发现异质性（P>0.05）。同时MR-Egger回归的截距项分析表明，这些SNP之间不存在水平多效性（P>0.05）。留一法通过逐一剔除单个SNP后，MR分析结果均未见明显改变。MR-PRESSO未见离群值。结论 代谢紊乱与原发性胆汁性胆管炎发生风险存在双向因果关联，二者互为风险因果。

Abstract

Objective A two-sample bidirectional Mendelian randomization (MR) analysis method was adopted to explore the causal relationship between metabolic disorder and primary biliary cholangitis. Methods Datasets on metabolic disorder and primary biliary cholangitis were sourced from the Genome-Wide Association Study website. The causal association between the two was determined using the analysis results of the inverse variance weighted (IVW) method, MR-Egger regression, simple mode, weighted mode, weighted median, and maximum likelihood ratio methods. Cochran's Q test examined single nucleotide polymorphism (SNP) heterogeneity, while the MR-Egger regression intercept analyzed SNP horizontal pleiotropy. The leave-one-out method was utilized for sensitivity analysis to ensure the result robustness. The Mendelian randomization pleiotropy residual sum and outlier test detected outliers among the included SNP. Results This study ultimately incorporated 8 SNP strongly associated with metabolic disorders and 39 SNP closely linked to primary biliary cholangitis. In forward MR analysis, with metabolic disorders as the exposure, the IVW results were statistically significant (OR=1.258, 95% CI: [1.016, 1.559], P<0.05), indicating an increased risk of primary biliary cholangitis due to metabolic disorders. In the reverse MR analysis, when primary biliary cholangitis was the exposure, the IVW results remained significant (OR=1.022, 95% CI: [1.003, 1.041], P<0.05), suggesting it elevated the risk of metabolic disorders. Cochran's Q test revealed no statistical heterogeneity in SNP related to either condition (P>0.05). MR-Egger regression intercept analysis indicated no horizontal pleiotropy among these SNP (P>0.05). The leave-one-out method, by removing each SNP individually, showed no significant changes in MR analysis results. Mendelian randomization pleiotropy residual sum and outlier detected no outliers. Conclusion Metabolic disorders increase the risk of primary biliary cholangitis, and primary biliary cholangitis also raises the risk of metabolic disorders. The two are causally related to each other.

关键词

代谢紊乱 / 原发性胆汁性胆管炎 / 孟德尔随机化 / 因果关系

Key words

metabolic disorder / primary biliary cholangitis / Mendelian randomization / causal relationship

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基金资助

甘肃省卫生健康行业科研资助项目(GSWSQN2023-02)