Socioecological Determinants of Immunoepigenetic Signatures of Diabetes Risk in Indigenous Communities

项目总结/摘要 夏威夷原住民和太平洋岛民（NHPIs）经历了不成比例的高患病率， 心脏代谢疾病，主要是2型糖尿病（DM），比其他美国种族/民族人群。 与白色居民相比，NHPI的糖尿病发病率高约2.5倍， DM差异在35岁时出现显著差异。NHPI的教育水平也最低， 实现，最低的平均收入，最高的贫困率，以及更高的风险暴露于DM风险因素相比， 其他主要种族/民族群体在夏威夷，也居住在环境，包括低邻里 社会经济地位（nSES）。糖尿病患病率差异与不良社会环境的巧合 涉及复杂的相互作用，可能影响与DM发病相关的基因途径。但 社会环境和生物学机制之间的相互作用是糖尿病健康差异的基础， NHPI未知。社会环境的不利影响，如nSES，可能包括增加 已知导致DM的慢性低度炎症的患病率。表观遗传机制（如DNA 甲基化）调节单核细胞的促炎基因（炎症的关键介质）的转录。我们 完成生活方式干预的NHPI糖尿病患者的初步数据显示， 相关的促炎基因的DNA甲基化和基因表达状态的变化 单核细胞炎症活性和血糖控制。在另一项研究中，我们发现 在NHPI青年中，肠道微生物组的变化，其生态失调也可能是DM的潜在属性， 相关的社会网络的影响和健康行为，改变他们的糖尿病风险。生活方式- 肠道微生物组的相关变化通过底物的生物利用度影响DNA甲基化 对表观遗传机制至关重要因此，我们提出一个假设，即社会环境条件 调节炎症和代谢途径的表观基因组景观和肠道微生物组组成 基础DM。为了验证这一假设，我们的目标是确定糖尿病患者单核细胞中糖尿病风险的表观遗传特征。 一组新的NHPI及其社交网络，并检查与邻里的关联， 人际层面的社会因素，采用横断面研究设计（目标1）。然后我们将探索 机械基础，该签名可能是先天DM相关性状的基础， 炎症、炎症活性和肠道微生物组组成/多样性（目标2）。最后，我们将确定 该特征可前瞻性预测DM结局的程度（目标3）。解决这些 目标将在健康不同的人群中产生新的NHPI数据集，以确定 社会环境背景下的“免疫表观遗传-肠道微生物组轴”和DM风险， 为NHPI中DM差异的病因学提供了新的见解，并对改善 早期发现糖尿病，以便在遭受社会/健康不平等的人群中实施预防策略。

PROJECT SUMMARY/ABSTRACT Native Hawaiians and Pacific Islanders (NHPIs) experience a disproportionately higher prevalence of cardiometabolic diseases, primarily Type-2 diabetes mellitus (DM), than other U.S. racial/ethnic populations. Compared to White residents, NHPIs have a ~2.5-fold higher incidence and earlier onset of diagnosed DM with significant differences in DM disparities appearing at age 35. NHPIs also have the lowest levels of educational attainment, lowest mean income, highest rates of poverty, and higher exposures to DM risk factors compared to other major racial/ethnic groups in Hawaii, and also reside in environments that include low neighborhood socioeconomic status (nSES). The coincidence of disparities in DM prevalence and adverse social environments implicate complex interactions that may impact gene pathways relevant to the onset of DM. However, the interactions between the social environment and biological mechanism(s) that underlie DM health disparities of NHPIs are unknown. The detrimental effects of social environments, such as nSES, may include an increased prevalence of chronic low-grade inflammation known to contribute to DM. Epigenetic mechanisms (e.g. DNA methylation) regulate transcription of pro-inflammatory genes of monocytes, a key mediator of inflammation. Our preliminary data in NHPIs with DM that completed a lifestyle intervention revealed significant genome-wide changes to the DNA methylation and gene expression states of pro-inflammatory genes that were associated with their monocyte inflammatory activity and glycemic control. In another study, we observed significant changes to the gut microbiome, dysbiosis of which may also be an underlying attribute of DM, in NHPI youth that correlated with social network influences and health behaviors that modified their risk for DM. Lifestyle- associated changes to the gut microbiome impacts DNA methylation through bioavailability of substrates essential to the epigenetic machinery. Thus, we propose a hypothesis that the social environment conditions the epigenomic landscape and gut microbiome composition that regulate inflammation and metabolic pathways underlying DM. To test this hypothesis, we aim to identify an epigenetic signature of DM risk in monocytes from a new cohort of NHPIs and that of their social networks, and examine associations with neighborhood- and interpersonal-level social factors using a cross-sectional study design (Aim 1). We will then explore the mechanistic basis to which this signature may underlie innate DM-relevant traits by examining associations with inflammation, inflammatory activity, and gut microbiome composition/diversity (Aim 2). Finally, we will determine the degree to which this signature may prospectively be predictive of DM outcome (Aim 3). Addressing these aims will yield novel datasets of NHPIs in a health disparate population for determining the relationship between the “immunoepigenetic-gut microbiome axis” and DM risk within the context of the social environment and provide new insight into the etiology of DM disparities in NHPIs, with generalizable implications for improving early identification of DM to enable preventative strategies in populations suffering from social/health inequities.