Socioecological Determinants of Immunoepigenetic Signatures of Diabetes Risk in Indigenous Communities

项目摘要/摘要 夏威夷原住民和太平洋岛民(NHPI)经历了不成比例的高发病率 心脏代谢性疾病，主要是2型糖尿病(DM)，比美国其他种族/民族人群更容易患上。 与白人居民相比，NHPI的发病率高出约2.5倍，被诊断为糖尿病的患者发病更早 糖尿病差异在35岁时出现显著差异。NHPI的教育水平也是最低的 最低平均收入、最高贫困率和更高的糖尿病风险因素风险暴露 夏威夷的其他主要种族/民族群体，也居住在包括低社区在内的环境中 社会经济地位(NSE)。糖尿病患病率差异与不利社会环境的重合 涉及复杂的相互作用，可能影响与糖尿病发病相关的基因通路。然而， 糖尿病健康差距形成的社会环境与生物机制的相互作用(S) NHPI是未知的。社会环境的有害影响，如NSE，可能包括增加 已知的与糖尿病有关的慢性低度炎症的流行。表观遗传机制(例如DNA 甲基化)调节单核细胞致炎基因的转录，单核细胞是炎症的关键介质。我们的 在完成生活方式干预的糖尿病患者的NHPI中的初步数据显示，全基因组显著 致炎相关基因DNA甲基化和基因表达状态的变化 单核细胞的炎症活性和血糖控制。在另一项研究中，我们观察到显著的 在NHPI青年中，肠道微生物群的变化，其微生物群落的失调也可能是DM的一个潜在属性 与社会网络影响和健康行为相关，从而改变了他们患糖尿病的风险。生活方式- 肠道微生物群的相关变化通过底物的生物利用度影响DNA甲基化 对于表观遗传机制来说是必不可少的。因此，我们提出了一个假设，即社会环境条件 调控炎症和代谢途径的表观基因组图景和肠道微生物组组成 潜在DM。为了验证这一假设，我们的目标是在单核细胞中识别DM风险的表观遗传学特征。 一组新的NHPI及其社交网络，并检查与邻居和 采用横断面研究设计的人际层面的社会因素(目标1)。然后我们将探索 这一特征可能构成先天糖尿病相关特征的机制基础，通过检查与 炎症、炎症活动和肠道微生物群组成/多样性(目标2)。最后，我们将确定 这一特征对糖尿病预后的预测性程度(目标3)。解决这些问题 AIMS将在健康不同的人群中产生新的NHPI数据集，以确定两者之间的关系 “免疫表观遗传-肠道微生物组轴”和糖尿病风险在社会环境和 对健康保险指标中糖尿病差异的病因提供了新的见解，并对改进具有普遍意义 及早发现糖尿病，以便在遭受社会/健康不平等之苦的人群中采取预防策略。

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.