Association between 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.