Epigenome modification by a dietary pattern rich in polyunsaturated fatty acids

修订后的项目摘要/摘要 这项拟议研究的总体目标是在食用传统饮食的阿拉斯加尤皮克原住民中确定与预防2型糖尿病(T2D)相关的生物途径的表观遗传学变化。Yup‘ik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，高达美国普通人群的20倍。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，Yupik人的代谢综合征(15%)和T2D(3%)的患病率仍然低于普通美国人。对尤皮克人来说，坚持传统的饮食模式可能会起到保护作用，尽管这种保护机制还不是很清楚。我们将使用氮稳定同位素比率(δ15N)作为传统饮食模式的一个有效的、客观的衡量标准来探索这些机制。 虽然在识别导致代谢性疾病的遗传因素方面已经取得了很大的进展，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。这项拟议的研究将使用光甲基化EPIC微阵列对来自569名处于传统饮食摄入量(DK104347)最高和最低十分之一的尤族人的存储外周血DNA样本进行精细定位，以揭示阵列数据中不明显的详细DNA甲基化模式，并识别影响这些基因甲基化的遗传变异。这些发现将在格陵兰因纽特人队列中重复，以确定来自尤皮克人的发现的普适性。候选基因甲基化模式的下游功能后果将使用基因表达分析来评估，这些样本来自于我们的饮食指标δ15N分布极端的个人。通过确定与坚持传统饮食和胰岛素敏感性相关的表观基因组生物标记物，拟议的研究将检验这样一个假设，即传统的尤普尼克饮食修改了关键基因的下游转录，这些关键基因有助于尤皮克人的新陈代谢健康。

Revised Project Summary/Abstract 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 fine map epigenetic biomarkers in the 20 most promising candidate genes identified using Illumina MethylationEPIC microarrays on stored peripheral blood DNA samples from 569 Yup’ik people at the highest and lowest deciles of traditional dietary intake (DK104347) using targeted bisulfite sequencing to reveal detailed DNA methylation patterns not apparent in the array data, and to identify genetic variants that influence methylation at these genes. These findings will be replicated in a Greenlandic Inuit cohort to determine the generalizability of the findings from Yup’ik people. The downstream functional consequences of methylation patterns in the candidate genes will be assessed using gene expression assays in 192 peripheral blood RNA samples from individuals at the extremes of the distribution of our dietary measure, δ15N. 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.