DNA Methylation and Metabolic Syndrome in Midlife Women of the ELEMENT Cohort

Background/Objectives: Metabolic syndrome (MetS) is a cluster of metabolic risk factors that markedly increase the risk of cardiovascular disease and type 2 diabetes. Its prevalence exceeds 50% among Mexican women. A growing number of studies suggest that DNA methylation, an epigenetic mechanism, is linked to MetS. Methylation risk scores (MRS) may be able to predict future disease risk, yet prospective studies with MRS and MetS are rare, especially in Hispanic populations. We aimed to (1) replicate previously reported locus-specific DNA methylation–MetS associations, (2) identify additional loci, and (3) evaluate an MRS for predicting MetS among a sample of midlife Mexican women. Methods: We analyzed 149 women from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort with DNA methylation measured in blood leukocytes collected around 2008 and MetS assessed approximately ten years later. Logistic regression was applied to a priori loci, and then all loci on the Infinium EPICv1 array. MRS performance was evaluated by cross-validation. Results: Four loci—probe ID cg11024682 (SREBF1), cg06500161 (ABCG1), cg22891070 (HIF3A), and cg02650017 (PHOSPHO1)—showed consistent associations with MetS. For example, each 1-percentage-point increase in methylation at cg11024682 (SREBF1) was associated with higher odds of MetS in the fully adjusted model (OR = 1.30; 95% CI: 1.12–1.52). No additional loci reached Bonferroni significance, though marginal associations with MetS components were observed. The MRS derived from four replicated loci was associated with higher odds of MetS per 1-SD increase in the training set (OR = 3.55; 95% CI: 2.03–6.22). In the independent testing set, the MRS-only model improved prediction compared with the baseline covariate-only model (AUC = 0.652 vs. 0.398; ΔAUC = +0.254). Conclusions: This study provides prospective evidence that specific DNA methylation markers are associated with MetS risk in midlife Mexican women. These loci, now replicated in several cohorts, are promising biomarkers for early identification and prevention of MetS.