Epigenomic Conditioning of Monocyte Inflammatory Activity in Native Hawaiians with Diabetes

项目摘要/摘要 这项应用的一个主要目标是了解环境和表观遗传的分子基础。 相互作用，从而影响潜在的炎症状态的2型糖尿病(DM)。原生的 夏威夷人和太平洋岛民(NHS/PI)的患病率高得不成比例，而且发病较早 DM的患病率高于其他民族。影响老年人NHS/PI的社会经济和生活方式因素 糖尿病的流行与全球DNA甲基化水平的改变有关，这是一种可能导致 在调节DM的慢性低度全身炎症方面发挥重要作用。的确， 炎症已被证明与外周血中的全局DNA高甲基化有关 单个核细胞(PBMC)，独立于DM的其他危险因素。有趣的是，差异DNA 外周血单核细胞中特定基因组基因的甲基化显示与免疫功能相关的基因和 炎症途径，与炎症的生物标志物相关。然而，中的异质性 外周血单核细胞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 甲基化与炎症有关。单核细胞在急性和慢性炎症中都发挥着核心作用， 在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甲基化调控PRO-2转录水平 单核细胞表达的炎性细胞因子。总之，这些研究表明，DNA甲基化 单核细胞的形态可能与细胞的炎症状态有关，这种状态可能在DM中发生改变 与炎症相对应。我们试图在NHS/PI中检查这种关系，这是以前从未发生过的 已经上报了。我们已经收集了初步数据，这些数据构成了假设的基础，与 健康个体，诊断为糖尿病的NHS/PI的单核细胞显示出独特的DNA甲基组图景， 这导致了他们高度的炎症反应。为了解决这一假设，我们建议访问 我们的多种族队列(MEC)，我们从其中获得详细的健康信息，并以可见的方式存入银行 冷冻保存的PBMCs和配对的血浆生物标本。我们的目标是(1)评估两者之间的关系 年龄和性别匹配的胰岛素抵抗、全身炎症和体外单核细胞炎症活性 健康(n=20)和糖尿病诊断(n=20)NHS/PI，以及(2)描述和比较 这些单核细胞，经过外周血单核细胞的浓缩，在全基因组范围内使用两个独立但互补的 接近了。我们预计，这些结果将在多大程度上揭示DNA甲基组景观 可能影响单核细胞的炎症活动，以及这种活动如何与糖尿病的已知危险因素相关联。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甲基化的差异。是这样的 研究将改变糖尿病健康差异的研究，以阐明表观遗传学病因。

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.