Epigenome modification by a dietary pattern rich in polyunsaturated fatty acids

这项拟议研究的总体目标是确定生物途径的表观遗传学变化。 与预防2型糖尿病(T2D)相关的尤皮克阿拉斯加原住民服用 传统饮食。Yupik传统饮食模式的特点是高蛋白、高脂肪和低 碳水化合物摄入量，以及n-3多不饱和脂肪酸水平，高达20倍于 普通的美国人口。尤皮克人高水平的传统食物摄入量与脂联素呈正相关，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，尤皮克人的饮食正在向更多地消费精加工市场食品过渡，超重和肥胖的流行开始反映出美国普通人口的情况。即便如此，代谢综合征(15%)和T2D(3%)的患病率 是的，这一数字仍然低于美国的总人口。坚持Yup‘ik传统饮食 模式在尤皮克人中可能是保护性的，尽管保护机制不是很好 明白了。我们将使用氮稳定同位素比率(δ15N)作为验证的、客观的测量 尽管在识别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，但只有不到10%的T2D表型的遗传力可以用已知的遗传变异来解释。表观遗传学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，从而为改变遗传易感性和洞察90%无法解释的遗传性提供了一种机制。拟议的研究将：1) 使用Illumina甲基化EPIC微阵列全面筛查&gt；850,000个甲基化位点 569名尤比克族人传统最高和最低等级外周血DNA样本 饮食摄入量；2)通过对20个最有希望的候选基因进行亚硫酸氢盐测序，精细定位甲基化位点 存储的192个Yup‘ik DNA样本中的区域，并确定192个存储的DNA样本中的发现的普适性 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 新收集的192名过去参与者的DNA样本的模式；以及4)在 新收集的来自192名过去参与者的RNA样本，这些参与者处于传统食物摄入量的极端情况下 确定与饮食结构和基因组改变相关的基因表达的下游变化 甲基化。通过识别与坚持传统饮食和饮食相关的表观基因组生物标志物 由于对胰岛素的敏感性，这项拟议的研究将检验传统的尤普尼克饮食会修改 促进尤皮克人代谢健康的关键基因的下游转录。

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.