Association of urinary copper and gestational diabetes mellitus: role of epigenome-wide DNA methylation and proteomics.

Context: The association between copper exposure and gestational diabetes mellitus (GDM) remains inconclusive.

Objectives: Our study aimed to investigate the prospective relationship between urinary copper and GDM and the mediating role of DNA methylation for this association.

Design: Nested case-control study based on the Tongjing-Huaxi-Shuangliu Birth Cohort.

Participants, exposure and main outcome measures: Urinary copper and genome-wide DNA methylations were measured in early pregnancy for 432 pregnant women, and 737 proteins were measured in a subset of 150 pregnant women.

Results: Urinary copper levels were positively associated with risk of GDM (adjusted odd ratio =1.48 for each one-unit increase in the log-transformed levels of copper, 95% confidence interval 1.15-1.91). 73 differential cytosine-phosphoguanine sites (CpGs) were identified to associate with copper. Of these CpGs, cg23773809 annotated to SNX10 mediated 24.7% and 22.4% of the copper-GDM and copper-1 h plasma glucose (1-h PG) association, respectively. cg04168577 annotated to PPFIBP2 and cg06105935 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.

Conclusions: 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.