Evaluating the causal effect of circulating proteome on the glycemic traits: Evidence from Mendelian randomization
Abstract
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.
Article Highlights
l Why did we undertake this study?
l Proteins are the key functional units of biology and disease and may play a role in abnormal glycemic traits.
l What is the specific question(s) we wanted to answer?
l To identify circulating proteins associated with glycemic traits using Mendelian randomization (MR)-based analytical framework.
l What did we find?
l We found multiple proteins that showed causal effects on abnormal glucose metabolism.
l What are the implications of our findings?
l These proteins may enhance the understanding of molecular etiology and provide insights into the screening, monitoring, and treatment of diabetes.