Trace element-linked DNA methylation sites and their association with type 2 diabetes and cardiovascular diseases:...

The trace elements (TEs) selenium, zinc, copper, manganese, iodine and iron are essential micronutrients that support essential metabolic functions. Imbalance in their homeostasis might contribute to the pathogenesis of major age-related chronic diseases including type 2 diabetes (T2D) and cardiovascular diseases (CVD). Emerging evidence suggests that TEs may affect health outcomes via epigenetic changes. However, few epigenome-wide association studies (EWAS) have explored TE-associated DNA methylation markers and their links to chronic disease outcomes.

We conducted TE-specific exploratory EWAS using a random subcohort (n = 1030) from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. The association between identified CpG sites and incident chronic diseases was evaluated using a case-cohort design comprising random subcohort participants and incident cases of T2D (n = 654) and CVD (n = 334). DNA methylation was measured with the MethylationEPIC BeadChip array. We used Prentice-weighted Cox proportional hazards regression models to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of TE-associated CpG sites with each incident chronic disease.

In the copper EWAS, we identified six CpG sites (cg00398673, cg03957124, cg05736499, cg07573872, cg11503550, and cg18513344) that were significantly associated with serum copper concentrations with a False Discovery Rate < 0.05. All associated CpG sites showed lower methylation levels in association with higher serum copper levels. Higher methylation levels of cg00398673 (HR per SD: 0.74, 95% CI 0.63-0.88), cg03957124 (HR per SD: 0.52, 95% CI 0.41-0.66), cg05736499 (HR Q5 vs Q1: 0.25, 95% CI 0.14-0.47), and cg18513344 (HR Q5 vs Q1: 0.37, 95% CI 0.24-0.57) were associated with decreased risk of developing T2D, and higher methylation levels of cg07573872 were associated with decreased risk of developing CVD (HR per SD: 0.85, 95% CI 0.72-0.99). We did not observe any CpG sites that were significantly associated with other TEs.

Serum copper levels are inversely associated with a number of CpG sites. Methylation levels at these CpG sites were inversely associated with developing T2D and CVD. These findings may provide new insights on understanding the increased risk of T2D and CVD with elevated blood copper levels.