Systems genetics analysis of cardiometabolic trait loci in humans

项目摘要 代谢综合征（MetSyn）是一组代谢状况，这些状况一起发生并促进代谢。 心血管疾病（CVD）和2型糖尿病的发展。虽然定义的各种标准 MetSyn存在，疾病状况包括腹型肥胖、胰岛素抵抗、血清甘油三酯升高 高密度脂蛋白（HDL）水平降低，血糖水平升高和高血压。 MetSyn的发病率预计将增加，因为肥胖已成为一种世界性的流行病。这种增加 可能会产生有害影响，实际上可能会逆转美国CVD下降的趋势。最近 全基因组关联研究（GWAS）已经确定了400多个基因组位点， 肥胖、糖尿病、心血管疾病和心脏代谢特征。然而，大多数潜在的基因和相关的 这些基因座如何促进疾病过程的机制仍然未知。 这项建议概述了一个综合系统遗传学的方法来确定因果基因和途径 通过结合来自广泛表型化的人类和小鼠队列的数据， 男性代谢综合征（METSIM）和杂交小鼠多样性小组（HMDP）研究的一部分， 分别它还概述了一个广泛的职业发展计划，供梅特·西韦莱克博士完成 在Aldons Lusis博士的指导下进行博士后培训，并过渡到独立的学术机构 通过建立心血管病理生理学的多学科研究计划， 在K99阶段的奖励，PI将测量脂肪mRNA和microRNA丰度使用 表达阵列和来自人类受试者的下一代谱分析，其将使用高表达水平进行基因分型。 密度SNP阵列。将在小鼠中进行类似的测量。显著基因型表达性状 在GWAS基因座的关联将被用于预测与疾病发展有因果关系的基因。共- 表达网络将从表达数据构建，并将用于预测 已知途径的致病基因。在预测了K99的致病基因及其功能后， 在授予阶段，PI将在R 00期间使用体外和体内实验来测试这些预测 奖的阶段。初步结果已经确定了编码RNA结合蛋白的CPEB 4， 5号染色体上腰臀比显著相关信号的致病基因， 人类体外研究和生物信息学方法将鉴定这种RNA靶向的mRNA 结合蛋白使用脂肪细胞特异性Cpeb 4转基因和基因敲除小鼠的体内研究将鉴定其在体内的表达。 在调节脂肪量和相关代谢性状中的作用。 拟议研究的总体目标是将系统生物学和分子分析结合起来， 体外和体内实验，导致对受干扰的基因网络的机械理解 与疾病相关的遗传变异导致心脏代谢紊乱。

PROJECT SUMMARY Metabolic syndrome (MetSyn) is a group of metabolic conditions that occur together and promote the development of cardiovascular disease (CVD) and type 2 diabetes. Although various criteria for defining MetSyn exist, disease conditions include abdominal obesity, insulin resistance, elevated serum triglyceride levels, depressed serum high-density lipoprotein (HDL) levels, elevated blood glucose levels and hypertension. The incidence of MetSyn is predicted to increase as obesity has become a worldwide epidemic. This increase may have detrimental effects and may actually reverse the trend of decreasing CVD in the US. Recent genome-wide association studies (GWAS) have identified over 400 genomic loci that are associated with obesity, diabetes, CVD and cardiometabolic traits. However, most of the underlying genes and the related mechanisms of how these loci contribute to the disease process remain unknown. This proposal outlines an integrated systems genetics approach to identify causal genes and pathways underlying the GWAS loci by combining data from extensively phenotyped human and mouse cohorts that are part of the Metabolic Syndrome in Men (METSIM) and Hybrid Mouse Diversity Panel (HMDP) studies, respectively. It also outlines an extensive career development plan for Dr. Mete Civelek to complete postdoctoral training under the mentorship of Dr. Aldons Lusis and transition to an independent academic position by establishing a multi-disciplinary research program in cardiovascular pathophysiology. During the K99 phase of the award, the PI will measure adipose mRNA and microRNA abundance using expression arrays and next generation profiling from the human subjects which will be genotyped using high density SNP arrays. Similar measurements will be performed in mice. Significant genotype-expression trait associations at GWAS loci will be used to predict genes causally involved in the development of disease. Co- expression networks will be constructed from expression data and will be used to predict the relationships of causal genes with known pathways. Having predicted the causal genes and their functions during the K99 phase of the award, the PI will then test these predictions, using in vitro and in vivo experiments during the R00 phase of the award. The preliminary results have identified CPEB4, which encodes an RNA binding protein, as the causal gene underlying the significant association signal in the chromosome 5 locus for waist-to-hip ratio in humans. In vitro studies and bioinformatics approaches will identify the mRNAs that are targeted by this RNA binding protein. In vivo studies using adipocyte specific Cpeb4 transgenic and knock-out mice will identify its role in the regulation of fat mass and associated metabolic traits. The overall goal of the proposed studies is to integrate system biology and molecular analysis in both in vitro and in vivo experiments, leading to mechanistic understandings of the gene networks that are perturbed by disease-associated genetic variants that result in cardiometabolic disorders.