Epigenome modification by a dietary pattern rich in polyunsaturated fatty acids

 描述(由申请人提供)：拟议研究的总体目标是确定Yup‘ik(阿拉斯加原住民)传统饮食保护作用下的表观基因组生物标志物和生物学机制，这种饮食富含来自海洋哺乳动物和鱼类的n-3多不饱和脂肪酸，与预防2型糖尿病(T2D)有关。尤皮克人高水平的传统食物摄入量与脂联素相关，与C反应蛋白、甘油三酯和瘦素/脂联素比率呈负相关，这表明胰岛素敏感性增加。然而，尤皮克人的饮食正在转变为增加市场上精加工食品的消费，超重和肥胖的流行现在反映了普通美国人的情况。即便如此，Yupik人的代谢综合征(15%)和T2D(3%)的患病率仍然低于美国普通人群。坚持Yup‘ik传统饮食模式的特点是高蛋白质和低碳水化合物的摄入量，EPA和DHA的摄入量是美国普通人群的20多倍。尽管传统的食物摄入可能对尤皮克人具有保护作用，但其保护机制还不是很清楚。我们将使用传统饮食模式的客观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%的糖尿病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：1)使用Illumina Megylation450微阵列，在传统饮食摄入量的最高和最低十分之一的576名尤皮克人的储存外周血DNA样本上全面筛选甲基化位点；2)通过对192个储存的尤皮克人DNA样本中最有希望的20个候选基因区域进行双硫代测序，精细绘制甲基化位点图，并验证192个储存的格陵兰因纽特人样本中的发现；3)通过评估新收集的150名过去参与者的DNA样本中的甲基化模式，评估表观遗传标记的稳定性；以及4)对新收集的150名过去参与者在传统食物摄入量极端情况下的RNA样本进行功能分析，以确定与饮食模式和基因组甲基化变化相关的基因表达的下游变化。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。

 DESCRIPTION (provided by applicant): The overall goal of the proposed research is to identify epigenomic biomarkers and biological mechanisms underlying the protective role of the Yup'ik (Alaska Native) traditional diet, which is rich in n-3 polyunsaturated fatty acids from marine mammals and fish and is associated with protection from type 2 diabetes (T2D). High levels of traditional food intake in Yup'ik people are 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 now mirrors 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 U.S. general population. Adherence to the Yup'ik traditional dietary pattern is characterized by high protein and low carbohydrate intakes, and intakes of EPA and DHA that surpass those of the U.S. general population by more than 20-fold. Although traditional food intake is likely to be protective in Yup'ik people, the mechanisms of protection are not well understood. We will use an 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 diabetes 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 Methylation450 microarrays to comprehensively screen for methylation sites on stored peripheral blood DNA samples from 576 Yup'ik people at the highest and lowest deciles of traditional dietary intake; 2) fine map methylation sites by bisulfit sequencing the 20 most promising candidate gene regions in 192 stored Yup'ik DNA samples and verify the findings in 192 stored Greenlandic Inuit samples; 3) assess the stability of epigenetic marks by evaluating methylation patterns in newly collected DNA samples from 150 past participants; and 4) perform functional analyses in newly collected RNA samples from 150 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.