DNA methylation markers of insulin resistance surrogate measures in the Atherosclerosis Risk in Communities (ARIC) study

Insulin resistance (IR) is a risk factor for cardiovascular diseases and type 2 diabetes. Associations between DNA methylation (DNAm) and IR have been less studied in African ancestry (AA) populations than those of European ancestry (EA). We aimed to identify associations between whole blood DNAm and IR in up to 1,811 AA and 964 EA participants from the Atherosclerosis Risk in Communities (ARIC) study. We quantified IR using three surrogate measures: the homeostasis model assessment of insulin resistance (HOMA-IR), the triglyceride-glucose index (TyG), and the triglyceride glucose-body mass index (TyG-BMI). We used ancestry-stratified linear regression models to conduct epigenome-wide association studies of IR, adjusting for batch effects and relevant covariates. Among 484,436 tested CpG sites, 39 were significantly associated with IR, of which 31% (10 in AA and two in EA) were associated with TyG-BMI and not previously reported for IR or related traits. These include a positive association at cg18335991-<i>SEMA7A</i> in AA. <i>SEMA7A</i> inhibits adipogenesis of preadipocytes and lipogenesis of mature adipocytes. DNAm levels at cg18335991 have been reported to be negatively associated with <i>SEMA7A</i> expression in blood. After additionally adjusting for smoking and drinking status, 15 of the 39 significant CpG sites remained significant or suggestive. Our study identified novel IR-associated CpG sites, contributing to a broader understanding of the epigenetic mechanisms underlying IR in diverse populations. Associations between DNA methylation (DNAm) and insulin resistance (IR) have been primarily studied in individuals of European ancestry. The epigenetic regulation of IR, quantified using different surrogate measures, has not been extensively reported in diverse populations.This study aimed to identify associations between DNAm and IR in African and European ancestries and assessed how these associations differ by IR surrogate measures.Among 39 significant IR-associated CpG sites, 12 CpG sites, associated with the triglyceride glucose-body mass index, were potentially novel, and most were detected in African ancestry participants.This study improves our understanding of the epigenetic mechanisms underlying IR in diverse populations. Associations between DNA methylation (DNAm) and insulin resistance (IR) have been primarily studied in individuals of European ancestry. The epigenetic regulation of IR, quantified using different surrogate measures, has not been extensively reported in diverse populations. This study aimed to identify associations between DNAm and IR in African and European ancestries and assessed how these associations differ by IR surrogate measures. Among 39 significant IR-associated CpG sites, 12 CpG sites, associated with the triglyceride glucose-body mass index, were potentially novel, and most were detected in African ancestry participants. This study improves our understanding of the epigenetic mechanisms underlying IR in diverse populations.