Evaluating the causal effect of circulating proteome on the glycemic traits: Evidence from Mendelian randomization

孟德尔随机化 全基因组关联研究 数量性状位点 生物 血糖性 蛋白质组 遗传关联 可药性 计算生物学 遗传学 生物信息学 糖尿病 遗传变异 单核苷酸多态性 内分泌学 基因 基因型
作者
Xing Xing,Siqi Xu,Yining Wang,Ziyuan Shen,Simin Wen,Yan Zhang,Guangfeng Ruan,Guoqi Cai
出处
期刊:Diabetes [American Diabetes Association]
被引量:3
标识
DOI:10.2337/db24-0262
摘要

Exploring the mechanisms underlying abnormal glycemic traits is important for deciphering type 2 diabetes and characterizing novel drug targets. This study aimed to decipher the causal associations of circulating proteins with fasting glucose (FG), 2-h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) using large-scale proteome-wide Mendelian randomization (MR) analyses. Genetic data on plasma proteomes were obtained from ten proteomic genome-wide association studies (GWAS). Both cis- and cis+trans-protein quantitative trait loci (pQTLs) MR analyses were conducted. Bayesian colocalization, Steiger filtering analysis, assessment of protein-altering variants, and mapping expression quantitative trait loci to protein quantitative trait loci were performed to investigate the reliability of the MR findings. Protein-protein interaction, pathway enrichment analysis, and evaluation of drug targets were performed. Thirty-three proteins were identified with causal effects on FG, FI, or HbA1c but not 2hGlu in the cis-pQTLs analysis, and 93 proteins had causal effects on glycemic traits in the cis+trans-pQTLs analysis. Most proteins were either considered druggable or drug targets. In conclusion, many novel circulating protein biomarkers were identified to be causally associated with glycemic traits. These biomarkers enhance the understanding of molecular etiology and provide insights into the screening, monitoring, and treatment of diabetes.
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