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.

中文翻译：

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评估循环蛋白质组对血糖性状的因果影响：来自孟德尔随机化的证据


探索异常血糖特征的潜在机制对于破译 2 型糖尿病和表征新药物靶点非常重要。本研究旨在使用大规模蛋白质组范围孟德尔随机化 （MR） 分析破译循环蛋白与空腹血糖 （FG） 、口服葡萄糖激发后 2 小时葡萄糖 （2hGlu） 、空腹胰岛素 （FI） 和糖化血红蛋白 （HbA1c） 的因果关系。血浆蛋白质组的遗传数据来自十项蛋白质组全基因组关联研究 （GWAS）。进行顺式和顺式+反式蛋白数量性状位点 （pQTLs） MR 分析。进行贝叶斯共定位、 Steiger 过滤分析、蛋白质改变变异的评估以及将表达数量性状位点映射到蛋白质数量性状位点，以研究 MR 结果的可靠性。进行蛋白质-蛋白质相互作用、通路富集分析和药物靶点评估。在 cis-pQTLs 分析中，鉴定出 33 种蛋白对 FG 、 FI 或 HbA1c 有因果影响，但对 2hGlu 无因果影响，在 cis+trans-pQTLs 分析中，93 种蛋白对血糖性状有因果影响。大多数蛋白质被认为是可成药的或药物靶点。总之，许多新的循环蛋白生物标志物被鉴定为与血糖性状有因果关系。这些生物标志物增强了对分子病因学的理解，并为糖尿病的筛查、监测和治疗提供了见解。