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.

胰岛素抵抗（Insulin resistance, IR）是心血管疾病与2型糖尿病的危险因素。相较于欧洲血统（European ancestry, EA）人群，非洲血统（African ancestry, AA）人群中DNA甲基化（DNA methylation, DNAm）与胰岛素抵抗的关联研究相对匮乏。本研究依托社区动脉粥样硬化风险（Atherosclerosis Risk in Communities, ARIC）研究的至多1811名非洲血统参与者与964名欧洲血统参与者，旨在探究全血DNA甲基化与胰岛素抵抗的关联。本研究采用三种替代指标量化胰岛素抵抗：胰岛素抵抗稳态模型评估（homeostasis model assessment of insulin resistance, HOMA-IR）、甘油三酯-葡萄糖指数（triglyceride-glucose index, TyG）以及甘油三酯葡萄糖-体重指数（triglyceride glucose-body mass index, TyG-BMI）。本研究采用血统分层线性回归模型开展胰岛素抵抗的表观全基因组关联研究，并校正批次效应与相关协变量。在484436个检测的CpG位点中，39个位点与胰岛素抵抗显著相关，其中31%（非洲血统人群中10个，欧洲血统人群中2个）与TyG-BMI相关，且此前未被报道与胰岛素抵抗或相关表型存在关联。这包括非洲血统人群中cg18335991-<i>SEMA7A</i>位点的正相关关联。<i>SEMA7A</i>可抑制前体脂肪细胞的成脂过程与成熟脂肪细胞的脂肪生成。已有研究表明，cg18335991位点的DNA甲基化水平与血液中<i>SEMA7A</i>的表达呈负相关。在额外校正吸烟与饮酒状态后，39个显著CpG位点中有15个仍保持显著或提示显著关联。本研究鉴定出了新的与胰岛素抵抗相关的CpG位点，有助于更全面地解析不同人群中胰岛素抵抗背后的表观遗传机制。此前的关联研究多聚焦于欧洲血统人群中DNA甲基化与胰岛素抵抗的关联。针对采用不同替代指标量化的胰岛素抵抗，其表观调控机制在多样化人群中尚未得到广泛报道。本研究旨在明确不同血统人群中DNA甲基化与胰岛素抵抗的关联，并评估这些关联因胰岛素抵抗替代指标不同而存在的差异。在39个与胰岛素抵抗显著相关的CpG位点中，12个与甘油三酯葡萄糖-体重指数相关的位点为潜在新发现位点，且多数在非洲血统参与者中被检测到。本研究加深了我们对多样化人群中胰岛素抵抗相关表观遗传机制的理解。此前的关联研究多聚焦于欧洲血统人群中DNA甲基化与胰岛素抵抗的关联。针对采用不同替代指标量化的胰岛素抵抗，其表观调控机制在多样化人群中尚未得到广泛报道。本研究旨在明确不同血统人群中DNA甲基化与胰岛素抵抗的关联，并评估这些关联因胰岛素抵抗替代指标不同而存在的差异。在39个与胰岛素抵抗显著相关的CpG位点中，12个与甘油三酯葡萄糖-体重指数相关的位点为潜在新发现位点，且多数在非洲血统参与者中被检测到。本研究加深了我们对多样化人群中胰岛素抵抗相关表观遗传机制的理解。