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）传统饮食保护作用的表观基因组生物标志物和生物学机制，该传统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，并与预防2型糖尿病（T2 D）相关。 在Yup'ik人中，高水平的传统食物摄入与脂联素相关，与C-反应蛋白、甘油三酯和瘦素：脂联素比率呈负相关，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，超重和肥胖的流行现在反映了美国普通人口的情况。即便如此，Yup'ik人的代谢综合征（15%）和T2 D（3%）的患病率仍然低于美国普通人群。遵循Yup'ik传统饮食模式的特点是高蛋白质和低碳水化合物摄入量，EPA和DHA摄入量超过美国普通人群20倍以上。尽管传统的食物摄入可能对Yup'ik人有保护作用，但保护机制尚不清楚。我们将使用传统饮食模式的客观测量来探索这些机制。 虽然在鉴定导致代谢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糖尿病表型的遗传性的不到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。拟议的研究将：1）使用Illumina Methylation 450微阵列对576名Yup'ik人在传统饮食摄入量的最高和最低十分位数下储存的外周血DNA样品上的甲基化位点进行全面筛查; 2）通过双硫测序对192个储存的Yup'ik DNA样品中最有希望的20个候选基因区域进行精细定位甲基化位点，并在192个储存的格陵兰因纽特人样品中验证发现; 3）通过评估来自150名过去参与者的新收集的DNA样品中的甲基化模式来评估表观遗传标记的稳定性;以及4）在传统食物摄入量的极端下，对来自150名过去参与者的新收集的RNA样品进行功能分析，以确定与饮食模式和改变的基因组甲基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志物，拟议的研究将测试传统Yup'ik饮食修改有助于Yup'ik人代谢健康的关键基因下游转录的假设。

 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.