Evaluating the Causal Effect of Circulating Proteome on Glycemic Traits: Evidence From Mendelian Randomization

• DOI: 10.2337/db24-0262
• Publication Date: 2024-10-17T17:41:47Z
• Authors: Xing Xing; Siqi Xu; Yining Wang; Ziyuan Shen; Simin Wen; Yan Zhang; Guangfeng Ruan; Guoqi Cai
• Keywords: Mendelian Randomization; Genome-wide Association Study; Proteome; Genetic Association; Druggability

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