Association between Urinary Copper and Gestational Diabetes Mellitus: Role of Epigenome-Wide DNA Methylation and Proteomics.

Abstract

The association between copper exposure and gestational diabetes mellitus (GDM) remains inconclusive. Our study aimed to investigate the prospective relationship between urinary copper and GDM and the mediating role of DNA methylation and proteomic biomarkers in this association. A nested case-control study was conducted based on the Tongji-Huaxi-Shuangliu Birth Cohort. Urinary copper levels and genome-wide DNA methylation were measured in early pregnancy for 432 pregnant women, and 737 circulating proteins were measured in a subset of 150 pregnant women. Urinary copper levels were positively associated with risk of GDM (adjusted odds ratio = 1.48 for each 1-unit increase in the log-transformed levels of copper, 95% CI, 1.15-1.91). A total of 73 differential cytosine-phosphoguanine sites (CpGs) were identified as associated with copper. Of these CpGs, cg23773809 annotated to SNX10 mediated 24.7% and 22.4% of the copper-GDM and copper-1 hour plasma glucose (1-h PG) association, respectively. cg04168577 annotated to PPFIBP2 and cg06105935 located in the intergenic region mediated 23.4% and 13.9% of the copper-1-h PG association, respectively. The protein CD2AP was found to be a reliable predictor for GDM. The 73 differential CpGs mediated 64.1% of the copper-CD2AP association. Copper exposure may induce alterations in DNA methylation patterns, which can subsequently lead to changes in the expression of proteins associated with GDM and elevate the risk of developing GDM.