Socioecological Determinants of Immunoepigenetic Signatures of Diabetes Risk in Indigenous Communities

原住民社区糖尿病风险免疫表观遗传特征的社会生态决定因素

• 批准号: 10458062
• 负责人: Alika Keolaokalani Maunakea
• 金额: $ 66.75万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-28 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458062
• 关键词: Address; Adult; Affect; Age; Behavioral; Biological; Biological Availability; Black race; Blood; Cardiometabolic Disease; Characteristics; Chronic; Complex; Cross-Sectional Studies; DNA Methylation; Data; Data Set; Development; Diabetes Mellitus; Diagnosis; Diet; Early identification; Educational Status; Elderly; Enrollment; Environment; Epigenetic Process; Ethnic group; Etiology; Exposure to; Filipino; Gene Expression; Genes; Genetic Transcription; Glycosylated hemoglobin A; Goals; Hawaii; Health; Health behavior; High Prevalence; Hispanic; Immunologic Factors; Incidence; Income; Indigenous; Individual; Inflammation; Inflammation Mediators; Inflammatory; Joints; Life Style; Measures; Mediating; Medical; Metabolic Pathway; Modeling; Native Americans; Native Hawaiian or Other Pacific Islander; Neighborhood Health Center; Neighborhoods; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Outcome Study; Participant; Pathway interactions; Persons; Plasma; Population; Poverty; Prediabetes syndrome; Prevalence; Prevention strategy; Research; Research Design; Risk; Risk Factors; Social Environment; Social Network; Socioeconomic Status; System; Testing; Youth; base; cohort; deprivation; diabetes risk; diabetic; dysbiosis; early onset; emerging adult; epigenetic regulation; epigenomics; experience; follow-up; genome-wide; glycemic control; gut microbiome; health disparity; health disparity populations; health inequalities; high risk population; immune function; improved; indigenous community; insight; lifestyle intervention; low socioeconomic status; medically underserved; microbiome composition; monocyte; multidisciplinary; non-diabetic; novel; prospective; racial and ethnic; recruit; segregation; social; social culture; social engagement; social factors; social influence; systemic inflammatory response; trait; underserved community

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.

项目概要/摘要 夏威夷原住民和太平洋岛民 (NHPI) 的患病率异常高 心脏代谢疾病，主要是 2 型糖尿病 (DM)，高于其他美国种族/族裔人群。 与白人居民相比，NHPI 的诊断 DM 发病率高出约 2.5 倍，且发病更早 35 岁时，DM 差异出现显着差异。NHPI 的教育水平也最低 与其他国家相比，他们的成就、最低平均收入、最高贫困率以及更高的 DM 风险因素 夏威夷的其他主要种族/族裔群体，并且也居住在包括低层社区的环境中 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 涉及可能影响与糖尿病发病相关的基因途径的复杂相互作用。然而， 造成 DM 健康差异的社会环境和生物机制之间的相互作用 NHPI 未知。社会环境（例如 nSES）的有害影响可能包括增加 已知可导致糖尿病的慢性低度炎症的流行。表观遗传机制（例如DNA 甲基化）调节单核细胞促炎基因的转录，单核细胞是炎症的关键介质。我们的 完成生活方式干预的糖尿病 NHPI 的初步数据揭示了显着的全基因组 相关促炎基因的 DNA 甲基化和基因表达状态的变化 及其单核细胞炎症活性和血糖控制。在另一项研究中，我们观察到显着 在 NHPI 青少年中，肠道微生物组发生变化，肠道菌群失调也可能是 DM 的一个潜在属性 与改变糖尿病风险的社交网络影响和健康行为相关。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：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 底层 DM。为了检验这一假设，我们的目标是鉴定单核细胞中 DM 风险的表观遗传特征。 一组新的 NHPI 及其社交网络，并检查与邻里和社区的关联 使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 通过检查与 炎症、炎症活动和肠道微生物组组成/多样性（目标 2）。最后，我们将确定 该特征可以在多大程度上预测 DM 结果（目标 3）。解决这些问题 目标将产生健康不同人群中 NHPI 的新数据集，用于确定之间的关系 社会环境背景下的“免疫表观遗传-肠道微生物组轴”和糖尿病风险 为 NHPI 中 DM 差异的病因学提供新的见解，对改善健康状况具有普遍意义 早期识别糖尿病，以便为遭受社会/健康不平等的人群制定预防策略。