DNA methylation in peripheral blood leukocytes for the association with glucose metabolism and invasive breast cancer

BACKGROUND: Insulin resistance (IR) is a well-established factor for breast cancer (BC) risk in postmenopausal women, but the interrelated molecular pathways on the methylome are not explicitly described. We conducted a population-level epigenome-wide association (EWA) study for DNA methylation (DNAm) probes that are associated with IR and prospectively correlated with BC development, both overall and in BC subtypes among postmenopausal women. METHODS: We used data from Women’s Health Initiative (WHI) ancillary studies for our EWA analyses and evaluated the associations of site-specific DNAm across the genome with IR phenotypes by multiple regressions adjusting for age and leukocyte heterogeneities. For our analysis of the top 20 IR-CpGs with BC risk, we used the WHI and the Cancer Genomic Atlas (TCGA), using multiple Cox proportional hazards and logit regressions, respectively, accounting for age, diabetes, obesity, leukocyte heterogeneities, and tumor purity (for TCGA). We further conducted a Gene Set Enrichment Analysis. RESULTS: We detected several EWA-CpGs in TXNIP, CPT1A, PHGDH, and ABCG1. In particular, cg19693031 in TXNIP was replicated in all IR phenotypes, measured by fasting levels of glucose, insulin, and homeostatic model assessment-IR. Of those replicated IR-genes, 3 genes (CPT1A, PHGDH, and ABCG1) were further correlated with BC risk; and 1 individual CpG (cg01676795 in POR) was commonly detected across the 2 cohorts. CONCLUSIONS: Our study contributes to better understanding of the interconnected molecular pathways on the methylome between IR and BC carcinogenesis and suggests potential use of DNAm markers in the peripheral blood cells as preventive targets to detect an at-risk group for IR and BC in postmenopausal women. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-023-01435-7.