血液代谢物与糖尿病肾脏疾病因果关系的孟德尔随机化研究  

A Mendelian randomized study on the causal relationship between blood metabolites and diabetic kidney disease

作　　者：朱玲玲 钮杰宇[2] 谭莹 佘云 余江毅 严倩华[1] ZHU Lingling;NIU Jieyu;TAN Ying;SHE Yun;YU Jiangyi;YAN Qianhua(Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210029,China;Nanjing University of Chinese Medicine,Nanjing 210023,China)

机构地区：[1]南京中医药大学附属医院,江苏南京210029 [2]南京中医药大学,江苏南京210023

出　　处：《海南医科大学学报》2025年第3期211-219,共9页Journal of Hainan Medical University

基　　金：国家自然科学基金项目(82004286);江苏省中医药管理局项目(ZT202206);江苏省研究生实践创新计划项目(SJCX23_0873)。

摘　　要：目的:采用两样本孟德尔随机化方法探索血液代谢物与糖尿病肾脏疾病(diabetic kidney disease,DKD)发病风险之间的因果关系。方法:一项涉及7824名参与者的全基因组关联研究(genomewide association study,GWAS)提供了486种人类血液代谢物的数据。初步分析使用了芬兰数据库的DKD GWAS数据,包含4111例欧洲病例和308539例对照。复制分析的DKD结局数据从IEU OpenGWAS project网站获取,包含1032例欧洲病例和452280例对照。使用逆方差加权法作为主要分析方法,辅以MR-Egger、加权中位数法。采用错误发现率进行多重比较控制假设检验水准。进行敏感性分析评估结果的可靠性。此外,还进行了连锁不平衡评分回归、steiger检验、复制及荟萃分析、混杂分析以全面验证因果关系。结果:γ-谷氨酰亮氨酸(OR=3.71,95%CI:1.23-11.18,P_(IVW)=0.0196,P_(FDR)=0.042)、羟色氨酸(OR=4.55,95%CI:1.81-11.48,P_(IVW)=0.0013,P_(FDR)=0.024)、辛酰基肉毒碱(OR=1.99,95%CI:1.11-3.58,P_(IVW)=0.0207,P_(FDR)=0.042)、1,7-二甲基尿酸(OR=1.74,95%CI:1.04-2.90,P_(IVW)=0.0351,P_(FDR)=0.045)、缓激肽(OR=1.19,95%CI:1.01-1.40,P_(IVW)=0.0428,P_(FDR)=0.047)及亚油酸二合物(OR=7.23,95%CI:1.07-48.59,P_(IVW)=0.042,P_(FDR)=0.047)与DKD发病风险呈正相关。敏感性分析结果稳健,结果不存在异质性和水平多效性。结论:本研究阐明了与DKD因果相关的特定血液代谢物,为疾病干预提供了潜在的靶点,并有助于其早期筛查和预防。Objective:To investigate the causal relationship between blood metabolites and the risk of diabetic kidney disease(DKD)by using two-sample Mendelian randomization analysis.Methods:A genome-wide association study(GWAS)involving 7824 participants provided information on 486 human blood metabolites.The preliminary analysis used DKD GWAS data from a Finnish database containing 4111 European cases and 308539 controls.DKD outcome data for replication analysis were obtained from the IEU OpenGWAS project website and included 1032 European cases and 452280 controls.Inverse variance weighting method was used as the main analysis method,supplemented by MR-Egger and weighted median method.Multiple comparisons were conducted using false discovery rate to control the level of hypothesis testing.Sensitivity analysis was performed to evaluate the reliability of the results.In addition,linkage disequilibrium score regression,steiger test,replication and meta-analysis,and confounding analysis were performed to fully verify causality.Results:γ-Glutamyl-leucine(OR=3.71,95%CI:1.23-11.18,P_(IVW)=0.0196,P_(FDR)=0.042),hydroxytryptophan(OR=4.55,95%CI:1.81-11.48,P_(IVW)=0.0013,P_(FDR)=0.024),octanoylcarnitine(OR=1.99,95%CI:1.11-3.58,P_(IVW)=0.0207,P_(FDR)=0.042),1,7-dimethyluric acid(OR=1.74,95%CI:1.04-2.90,P_(IVW)=0.0351,P_(FDR)=0.045),bradykinin(OR=1.19,95%CI:1.01-1.40,P_(IVW)=0.0428,P_(FDR)=0.047)and dihomo-linoleate(OR=7.23,95%CI:1.07-48.59,P_(IVW)=0.042,P_(FDR)=0.047)were positivelycorrelated with the risk of DKD.The results of sensitivity analysis were robust and there was no heterogeneity or horizontal pleiotropy.Conclusion:This study elucidates specific blood metabolites causally associated with DKD,providing potential targets for intervention and contributing to its early screening and prevention.

关 键 词：血液代谢物 糖尿病肾脏疾病 因果推断 孟德尔随机化 

分 类 号：R587.2[医药卫生—内分泌] R692.9[医药卫生—内科学]