Epigenome modification by a dietary pattern rich in polyunsaturated fatty acids

拟议研究的总体目标是确定生物途径中的表观遗传变化 与保护2型糖尿病（T2 D）有关的Yup'ik阿拉斯加土著人消费 传统饮食Yup'ik的传统饮食模式的特点是高蛋白，高脂肪，低脂肪，高蛋白，低脂肪，高脂肪，低脂肪，高脂肪，高脂肪 碳水化合物的摄入量，以及n-3多不饱和脂肪酸的水平，高达20倍以上， 美国的一般人口。在Yup'ik人中，高水平的传统食物摄入与脂联素呈正相关，与C-反应蛋白、甘油三酯和瘦素：脂联素比率呈负相关，提示胰岛素敏感性增加。然而，Yup'ik人的饮食正在过渡到增加对高度加工的市场食品的消费，超重和肥胖的流行开始反映美国普通人口的情况。即便如此，代谢综合征（15%）和2型糖尿病（3%）的患病率， Yup'ik人仍然低于美国总人口。遵守Yup'ik传统饮食 在Yup'ik人中，模式可能具有保护作用，尽管保护机制并不完善 明白我们将使用氮稳定同位素比（δ 15 N）作为一个有效的，客观的措施， 尽管在鉴定导致代谢性疾病的遗传因素方面已经取得了相当大的进展，但已知的遗传变异解释了T2 D表型的遗传力的不到10%。表观遗传机制最近被认为是遗传风险和环境暴露（如饮食）之间的联系，从而为遗传易感性的改变提供了一种机制，并深入了解了90%尚未解释的遗传性。本研究将：（1） 使用Illumina MethylationEPIC微阵列全面筛选储存的> 850，000个甲基化位点， 来自569名Yup'ik人的外周血DNA样本，在传统的最高和最低十分位数中， 饮食摄入; 2）通过亚硫酸氢盐测序20个最有希望的候选基因的精细甲基化位点图 区域在192个存储的Yup'ik DNA样本，并确定在192个存储的结果的普遍性， 格陵兰因纽特人DNA样本; 3）通过评估甲基化来评估表观遗传标记的稳定性 从192名过去的参与者中新收集的DNA样本中的模式;以及4）在 新收集的RNA样本来自192名过去的参与者，他们处于传统食物摄入量的极端， 确定与饮食模式和基因组改变相关的基因表达的下游变化 甲基化通过鉴定与坚持传统饮食相关的表观基因组生物标志物， 与胰岛素敏感性，拟议的研究将测试假设，传统的Yup'ik饮食修改 关键基因的下游转录，有助于Yup'ik人的代谢健康。

The overall goal of the proposed research is to identify epigenetic changes in biological pathways associated with protection from Type 2 Diabetes (T2D) in Yup’ik Alaska Native people consuming a traditional diet. The Yup’ik traditional dietary pattern is characterized by high protein, high fat, and low carbohydrate intakes, as well as n-3 polyunsaturated fatty acid levels that are up to 20 times higher than in the general U.S. population. High levels of traditional food intake in Yup’ik people are positively associated with adiponectin and inversely associated with c-reactive protein, triglycerides, and the leptin:adiponectin ratio, suggestive of increased insulin sensitivity. However, the diet of Yup’ik people is transitioning to increased consumption of highly processed market foods, and the prevalence of overweight and obesity is beginning to mirror that of the general U.S. population. Even so, the prevalence of metabolic syndrome (15%) and T2D (3%) among Yup’ik people remains lower than in the general U.S. population. Adherence to a Yup’ik traditional dietary pattern is likely to be protective in Yup’ik people, although the mechanisms of protection are not well understood. We will use the nitrogen stable isotope ratio (δ15N) as a validated, objective measure of the traditional dietary pattern to explore these mechanisms.Although considerable advances have been made in the identification of genetic factors contributing to metabolic diseases, less than 10% of the heritability of T2D phenotypes is explained by known genetic variation. Epigenetic mechanisms have recently been proposed as a link between genetic risk and environmental exposures such as diet, thereby providing a mechanism for the modification of genetic predisposition and insight into 90% of the heritability that is not explained. The proposed research will: 1) use Illumina MethylationEPIC microarrays to comprehensively screen >850,000 methylation sites on stored peripheral blood DNA samples from 569 Yup’ik people at the highest and lowest deciles of traditional dietary intake; 2) fine map methylation sites by bisulfite sequencing the 20 most promising candidate gene regions in 192 stored Yup’ik DNA samples and determine the generalizability of the findings in 192 stored Greenlandic Inuit DNA samples; 3) assess the stability of epigenetic marks by evaluating methylation patterns in newly collected DNA samples from 192 past participants; and 4) perform functional analyses in newly collected RNA samples from 192 past participants at the extremes of traditional food intake to determine the downstream changes in gene expression associated with dietary pattern and altered genomic methylation. By identifying epigenomic biomarkers associated both with adherence to a traditional diet and with insulin sensitivity, the proposed research will test the hypothesis that a traditional Yup’ik diet modifies the downstream transcription of key genes that contribute to metabolic health of Yup’ik people.