基于孟德尔随机化探讨血清代谢组学与病毒性肝炎的关联

Exploring the association between serum metabolomics and viral hepatitis based on Mendelian randomization

目的:病毒性肝炎(VH)可能导致肝功能严重受损。而血清代谢物与VH的关系尚未明确。本研究旨在利用孟德尔随机化(MR)方法探索血清代谢物与VH之间的潜在关联。方法:利用逆方差加权法(IVW)、加权中位数法、MR-Egger回归法、加权模式以及简单模式5种MR分析方法,对全基因组关联研究(GWAS)Catalog数据库中的血清代谢组数据和FinnGen R 10版本中的VH GWAS数据进行两样本双向MR分析。借助Power统计值来评估当前MR结果的统计功效,采用Cochran s Q检验、MR-Egger回归、MR-PRESSO、Steiger检验和留一法来进行敏感性分析。对正向MR分析中发现与VH有因果关系的血清代谢物进行了单独的反向MR分析。对具有显著因果关系的代谢物进行通路富集分析。结果:在进行错误发现率(FDR)矫正后,根据IVW结果共发现8种与VH发生风险相关的血清代谢物。其中谷氨酰胺、十四酸盐、缬氨酸及4-甲基-2-氧代戊酸是VH发生的潜在保护性代谢物;而肌醇、胆酸盐、吡哆醇、γ-生育酚与VH存在显著因果关系。同时VH十四酸盐的水平显著升高。所有的结果均不存在异质性及水平多效性。此外,抗坏血酸和丙二酸代谢以及维生素B6通路是代谢物与VH关系的主要作用通路。结论:血清代谢物与VH存在显著关联,通过对血清代谢物的监测与调控,或许可以对VH进行预防、监测和治疗。

Objective:Viral hepatitis(VH)may lead to severe impairment of liver function.And the relationship between serum metabolites and VH has not been clarified.The aim of this study is to explore the potential association between serum metabolites and VH using Mendelian randomization(MR).Methods:A two-sample bidirectional MR analysis was conducted using serum metabolites data from the Genome-Wide Association Study Catalog(GWAS Catalog)and VH data from the FinnGen R 10.5 MR methods were applied:inverse variance weighting(IVW),weighted median,MR-Egger regression,weighted mode,and simple mode.The statistical power of the MR results was evaluated using power statistics.Sensitivity analyses were conducted with Cochran's Q test,MR-Egger regression,MR-PRESSO,Steiger's test,and the leave-one-out method.Separate reverse MR analyses were conducted on serum metabolites that demonstrated a causal association with VH in the forward MR analysis.Finally,a pathway enrichment analysis was performed for metabolites with significant causal associations.Results:After applying false discovery rate(FDR)correction,eight serum metabolites were identified as being associated with the risk of VH based on IVW results.Glutamine,tetradecanoate,valine,and 4-methyl-2-oxovaleric acid were identified as potential protective metabolites against VH.In contrast,inositol,cholate,pyridoxine,andγ-tocopherol were significantly associated with an increased risk of VH.The level of tetradecanoate was also significantly elevated post-VH.All findings were free from heterogeneity and pleiotropy.Furthermore,ascorbate and malonate metabolism,as well as the vitamin B6 pathway,were identified as key metabolic pathways linking these metabolites to VH.Conclusion:Serum metabolites show a significant association with VH,suggesting that monitoring and regulating these metabolites could help in the prevention,diagnosis,and treatment of VH.