南方医科大学学报2026，Vol.46Issue(2)：278-285,8.DOI:10.12122/j.issn.1673-4254.2026.02.05
血浆代谢物介导炎症蛋白对阿尔茨海默病的因果效应:一项孟德尔随机化分析研究
Plasma metabolites mediates the causal effect of inflammatory proteins on Alzheimer's disease:a Mendelian randomization study
摘要
Abstract
Objective To investigate the causal relationship between inflammatory proteins and Alzheimer's disease(AD)and the mediating role of plasma metabolites therein.Methods Using Mendelian mandomization(MR)methods and publicly available genome-wide association study(GWAS)data,we selected 91 single nucleotide polymorphisms(SNPs)that were strongly linked to inflammatory proteins without reverse causality with AD as the outcome.A bidirectional two-sample MR analysis was performed.Inflammatory proteins with causal links to AD were identified via inverse variance weighted(IVW)analysis.A mediation MR analysis was then performed using 1400 plasma metabolites to assess their mediating role in this causal pathway.Results The preliminary bidirectional MR analysis identified 3 inflammatory proteins that had a potential positive causal association with AD without reverse causality:Axin-1,C-X-C motif chemokine ligand 11(CXCL11),and interleukin-12β(IL-12β).Elevated levels of Axin-1 were positively causally associated with AD risk(OR=1.082,95%CI:1.009-1.159;P=0.026),while CXCL11(OR=0.951,95%CI:0.914-0.990;P=0.026)and IL-12β(OR=0.959,95%CI:0.926-0.994;P=0.026)were negatively causally associated with AD risk.Sensitivity analyses indicated that these causal effects exhibited no heterogeneity or pleiotropy.In the mediation analysis,18 plasma metabolites with causal links to AD were identified,among which 3 plasma metabolites exhibited mediating effects in the inflammatory protein-AD causal relationship.Methyl-4-hydroxybenzoate sulfate partially mediated the effect between Axin-1 and AD(20.10%).Pregnenetriol sulfate partially mediated the effect between CXCL11 and AD(18.20%).The ratio of spermidine to ornithine played an important mediating role between IL-12β and AD,with a mediating effect of 43.40%.Conclusion This study reveals how specific inflammatory proteins influence AD risk via plasma metabolites and provides genetic evidence for inflammatory-metabolic interactions in AD to facilitate the identification of potential biomarkers and targets for early detection and intervention of AD.关键词
炎症蛋白/血浆代谢物/孟德尔随机化/阿尔茨海默病/中介效应Key words
inflammatory proteins/plasma metabolites/mendelian randomization/Alzheimer's disease/mediating effect引用本文复制引用
陈梅妹,黄睿娜,杨朝阳..血浆代谢物介导炎症蛋白对阿尔茨海默病的因果效应:一项孟德尔随机化分析研究[J].南方医科大学学报,2026,46(2):278-285,8.基金项目
福建省自然科学基金(2022J01361) （2022J01361）
福建中医药大学基础学科提升项目(XJC2023004) （XJC2023004）
