Epigenomic Conditioning of Monocyte Inflammatory Activity in Native Hawaiians with Diabetes

项目总结/摘要 该应用的主要目标是了解环境和表观遗传的分子基础 因此影响2型糖尿病（DM）潜在的炎症状态的相互作用。原生 夏威夷人和太平洋岛民（NHs/PI）的患病率不成比例地更高， 比其他种族的人多。社会经济和生活方式因素赋予NHs/PI的提高 糖尿病的患病率与DNA甲基化的总体水平改变有关，这是一种表观遗传机制， 在调节DM的慢性低度全身性炎症特征中起主要作用。的确， 炎症已被证明与外周血中的整体DNA超甲基化有关 单核细胞（PBMC），独立于其他糖尿病风险因素。有趣的是， PBMC中特定基因组位点的甲基化表现出与免疫功能相关的基因的变化， 炎症途径，其与炎症的生物标志物相关。然而， PBMC的细胞类型组成使得很难确定这些观察到的DNA差异是如何产生的。 甲基化与炎症有关。单核细胞在急性和慢性炎症中都起着中心作用， 在用Toll样受体配体刺激后分泌各种促炎细胞因子，因此是一种 全身炎症的主要来源。DNA甲基化调节前- 单核细胞表达的炎性细胞因子。总之，这些研究表明， 单核细胞的景观可能与细胞的炎症状态有关，这可能在DM中改变 与炎症相对应。我们试图在NH/PI中研究这种关系，这是以前从未有过的。 被举报。我们已经收集了初步数据，这些数据构成了假设的基础， 在健康个体中，来自诊断为DM的NH/PI的单核细胞表现出独特的DNA甲基化景观， 从而调节他们的炎症反应为了解决这一假设，我们建议访问 我们的多种族队列（MEC），我们有详细的健康信息，并有可行的银行 冷冻保存的PBMC和配对的血浆生物样本。我们的目标是：（1）评估 胰岛素抵抗、全身炎症和离体单核细胞炎症活性 健康（n=20）和DM诊断（n=20）的NH/PI，和（2）表征和比较 这些单核细胞，从PBMC富集后，使用两个独立但互补的全基因组 接近。我们预计，这些结果将告知DNA甲基化景观的程度， 可能调节单核细胞的炎症活动，以及这与已知的糖尿病危险因素的关系。这 这项研究将为未来研究单核细胞功能差异的程度奠定基础。 可能归因于我们MEC中5个不同种族/民族之间DNA甲基化的变异性。等 研究将改变糖尿病健康差异的研究，以阐明表观遗传病因。

PROJECT SUMMARY/ABSTRACT A primary goal of this application is to understand the molecular basis of environmental and epigenetic interactions that consequently influence inflammatory states underlying Type-2 diabetes mellitus (DM). Native Hawaiians and Pacific Islanders (NHs/PIs) experience a disproportionately higher prevalence and earlier onset of DM than other ethnic groups. The socioeconomic and lifestyle factors conferring NHs/PIs to the heightened prevalence of DM associate with altered global levels of DNA methylation, an epigenetic mechanism likely to play a major role in regulating the chronic low-grade systemic inflammation characteristic of DM. Indeed, inflammation has been shown to be associated with global DNA hypermethylation in peripheral blood mononuclear cells (PBMCs), independent of other risk factors for DM. Interestingly, differential DNA methylation at specific genomic loci in PBMCs exhibited changes at genes related to immune function and inflammatory pathways, which are associated with biomarkers of inflammation. However, the heterogeneity in cell type composition of PBMCs makes it difficult to determine how these observed differences in DNA methylation associate with inflammation. Monocytes play a central role in both acute and chronic inflammation, secreting various pro-inflammatory cytokines after stimulation with toll like receptor ligands, and are thus a major source of systemic inflammation. DNA methylation regulates the transcriptional levels of pro- inflammatory cytokines expressed by monocytes. Together, these studies suggest that the DNA methylation landscape of monocytes may be associated with inflammatory states of the cells, which may be altered in DM to correspond with inflammation. We seek to examine this relationship in NHs/PIs, which has never before been reported. We have collected preliminary data that form the basis for the hypothesis that compared to healthy individuals, monocytes from NHs/PIs diagnosed with DM exhibit a distinct DNA methylomic landscape, which conditions their heightened inflammatory response. To address this hypothesis, we propose to access our Multiethnic Cohort (MEC), from which we have detailed health information, and banked viably cryopreserved PBMCs and paired plasma biospecimens. We aim to (1) evaluate the relationships between insulin resistance, systemic inflammation, and ex vivo monocyte inflammatory activity in age- and sex-matched healthy (n=20) and DM-diagnosed (n=20) NHs/PIs, and (2) characterize and compare the DNA methylomes of these monocytes, following enrichment from PBMCs, using two independent yet complementary genome-wide approaches. We anticipate that these results will inform the extent to which the DNA methylomic landscape may condition monocyte inflammatory activity and how this associates with known risk factors for DM. This study will form the foundation for future work investigating the extent to which differences in monocyte function may be attributed to variability in DNA methylation between 5 distinct racial/ethnic groups in our MEC. Such studies would transform DM health disparities research to elucidate an epigenetic etiology.