3012-LB: Sex-Specific Epigenome-Wide Association Study of Type 2 Diabetes

Introduction and Objective: DNA methylation differences have been associated with type 2 diabetes (T2D), with limited reproducibility and assessment of sex-specific epigenetic architecture. Methods: We conducted an epigenome-wide association study (EWAS) of prevalent T2D (313 cases; 3,176 controls) using Illumina MethylationEPIC 850K data from the Personalized Environment and Genes Study, a population-based North Carolina cohort. Robust linear regression models were applied in combined, sex-stratified, and ancestry-stratified analyses. To assess sample size imbalance, females were randomly down-sampled 10x to match the male sample size, and genomic inflation factors were calculated. Sex-specific heterogeneity was evaluated via inverse-variance weighted meta-analysis. Sensitivity analyses adjusted for BMI, smoking, income, and rurality, and reproducibility was assessed using two independent EWAS datasets. Results: We identified 2,306 genome-wide significant CpGs (P < 1×10-7) in the combined analysis. Sex-stratified results revealed 1,468 significant CpGs in females, including established loci (TXNIP, ABCG1, SOCS3) and novel signals (NOD2, SRF, PIEZO1), versus 9 in males. Female down-sampling confirmed that disparity was not attributable to power alone (mean female λ=1.69 vs male λ=1.24), supporting sex-specific biology. Approximately 27% of combined-significant CpGs exhibited significant between-sex heterogeneity compared with ~3% showing ancestry-based heterogeneity. Across all sensitivity models, females consistently demonstrated substantially more significant associations than males. CpG signals showed strong reproducibility, with 100% concordant effect direction among genome-wide significant CpGs shared with both Hillary et al. and Kulkarni et al., and 96.6% concordance with Hillary et al. at nominal significance. Conclusion: These findings reveal a reproducible, markedly sex-specific whole-blood DNA methylation signature of T2D and emphasize the need for sex-aware epigenomic analyses in metabolic disease research. Disclosure J. Breeyear: None. C. Campbell: None. Z. Xu: None. F. Akhtari: None. K.M. Walsh: None. R.P. Woychik: None. J. House: None. A. Motsinger-Reif: None. Funding This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The contributions of the NIH author(s) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.