Social Immunoepigenetic Conditioning of Diabetes Disparities

项目总结/摘要 夏威夷原住民和太平洋岛民（NHs/PI）的患病率不成比例地高 和早发心脏代谢健康结局，包括2型糖尿病（DM）和 心血管疾病（CVD），比其他种族/民族群体。这些健康差异可能是由于 形成个人健康行为的社会环境（如营养、体育活动和教育）; 可能介导基因-环境相互作用的生理反应。社会的不利影响 环境的变化可能包括全身炎症的增加，全身炎症是心脏代谢疾病的标志， 免疫系统的单核细胞起主要作用。我们观察了社区的社会环境， 与脆弱人群的炎症有关。此外，其他研究表明，单核细胞- 介导的炎症导致靶细胞中的胰岛素抵抗， 疾病表观遗传机制，包括DNA甲基化，调节促炎因子的转录 单核细胞中的基因。我们认为，邻里社会环境导致DNA的全球变化 与心脏代谢疾病风险相关的免疫细胞甲基化状态。在工作中，我们观察到 促炎基因的DNA甲基化和基因表达状态的显著全基因组变化 与糖尿病患者单核细胞炎症活性和血糖控制相关， 单核细胞中胰岛素抵抗的甲基化特征与CVD风险相关。这些数据一起 这表明心脏代谢疾病可能部分是由于社会环境引起的 表观基因组景观单核细胞潜在的炎症状态。在这项研究中，我们将讨论 社区社会环境是否影响不同年龄组单核细胞的表观基因组变异性， 在夏威夷的少数民族人群中， NHS/PI。要做到这一点，我们建议整合详细的个人层面的健康行为，临床/免疫学， 遗传和单核细胞特异性表观基因组数据与社区水平的社会环境数据， 多种族队列研究（MEC）。通过使用一项以人群为基础的前瞻性研究， 将有一个前所未有的机会来研究表观基因组信息的翻译效用， 预测20年随访期间发生的临床诊断的DM。由于NHS/PI 不成比例的高糖尿病发病率，我们预计免疫表观遗传标记的频率增加， 预测糖尿病的结果，这将提供新的洞察健康差异的病因。因此，我们认为， 我们相信，我们的社会表观基因组多种族研究符合本FOA的总体目标， 表观基因组学关注健康差异，扩大理解表观遗传机制的方法 社会因素导致生物变化，影响健康差异，并促进表观遗传学 开展研究，以更好地诊断弱势群体的疾病风险或复原力。

PROJECT SUMMARY/ABSTRACT Native Hawaiians and Pacific Islanders (NHs/PIs) experience a disproportionately higher prevalence and earlier onset of cardiometabolic health outcomes, including Type-2 diabetes mellitus (DM) and cardiovascular disease (CVD), than other racial/ethnic groups. These health disparities may result from the social environment shaping an individual’s health behaviors (e.g. nutrition, physical activity, and education) and physiological responses that may mediate gene-environment interactions. The detrimental effects of social environments may include an increase in systemic inflammation, a hallmark of cardiometabolic diseases where monocytes of the immune system play a major role. We observed neighborhood social environments that associated with inflammation in vulnerable populations. Additionally, other studies show that monocyte- mediated inflammation leads to insulin resistance in target cells and heightened risk of cardiometabolic diseases. Epigenetic mechanisms, including DNA methylation, regulate transcription of pro-inflammatory genes in monocytes. We posit that neighborhood social environment leads to global changes in DNA methylation states in immune cells associated with cardiometabolic disease risk. In our work, we observed significant genome-wide changes to DNA methylation and gene expression states of pro-inflammatory genes that associated with monocyte inflammatory activity and glycemic control in DM patients, and a robust DNA methylomic signature of insulin resistance in monocytes that correlated with CVD risk. Together, these data suggest that cardiometabolic diseases may in part result from social environment-induced changes to the epigenomic landscape in monocytes underlying their inflammatory states. In this study, we will address whether the neighborhood social environment impacts epigenomic variability in monocytes across different ethnic populations in Hawaii and account for cardiometabolic health disparities, specifically to that of DM in NHs/PIs. To do so, we propose to integrate detailed individual-level health behavior, clinical/immunologic, genetic, and monocyte-specific epigenomic data with neighborhood-level social environment data from our Multiethnic Cohort Study (MEC). By using a population-based prospective study with viably preserved cells, we will have an unprecedented opportunity to examine the translational utility of epigenomic information in predicting clinically diagnosed DM that occurred during a 20-year follow-up. As NHs/PIs have disproportionately high rates of DM, we anticipate an increased frequency of an immunoepigenetic signature predictive of DM outcomes, which would provide novel insight into the etiology of health disparities. Therefore, we believe our social epigenomic multiethnic study meets the overall goals of this FOA to advance the science of epigenomics focused on health disparities, expand approaches for understanding epigenetic mechanisms by which social factors lead to biological changes that affect health disparities, and promote epigenetics research to better diagnose disease risk or resiliency among disadvantaged populations.