Systems genetics analysis of cardiometabolic trait loci in humans

描述（由申请人提供）：代谢综合征（MetSyn）是一组同时发生并促进心血管疾病（CVD）和2型糖尿病发展的代谢疾病。尽管存在用于定义MetSyn的各种标准，但疾病状况包括腹部肥胖、胰岛素抗性、血清甘油三酯水平升高、血清高密度脂蛋白（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不利影响，实际上可能会逆转美国CVD下降的趋势。最近的全基因组关联研究（GWAS）已经确定了400多个与肥胖、糖尿病、CVD和心脏代谢性状相关的基因组位点。然而，大多数潜在的基因和这些基因座如何促进疾病过程的相关机制仍然未知。 该提案概述了一种综合系统遗传学方法，通过结合来自广泛表型的人类和小鼠队列的数据来识别GWAS基因座的致病基因和途径，这些数据分别是男性代谢综合征（METSIM）和杂交小鼠多样性小组（HMDP）研究的一部分。它还概述了Mete Civelek博士的广泛职业发展计划，以便在Aldons Lusis博士的指导下完成博士后培训，并通过建立心血管病理生理学的多学科研究计划过渡到独立的学术职位。 在该奖项的K99阶段，PI将使用表达阵列测量脂肪mRNA和microRNA丰度，并使用高密度SNP阵列对人类受试者进行基因分型。将在小鼠中进行类似的测量。GWAS基因座的显著基因型-表达性状关联将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，并将用于预测因果基因与已知途径的关系。在奖项的K99阶段预测了因果基因及其功能后，PI将在奖项的R 00阶段使用体外和体内实验来测试这些预测。初步结果已经确定编码RNA结合蛋白的CPEB 4是人类腰臀比5号染色体基因座中重要关联信号的致病基因。体外 研究和生物信息学方法将鉴定这种RNA结合蛋白靶向的mRNA。使用脂肪细胞特异性Cpeb 4转基因和敲除小鼠的体内研究将确定其在脂肪量和相关代谢性状的调节中的作用。 拟议研究的总体目标是在体外和体内实验中整合系统生物学和分子分析，从而对导致心脏代谢紊乱的疾病相关遗传变异所干扰的基因网络进行机械理解。

DESCRIPTION (provided by applicant): 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.