Systems genetics analysis of cardiometabolic trait loci in humans

描述(申请人提供)：代谢综合征(MetSyn)是一组共同发生并促进心血管疾病(CVD)和2型糖尿病发展的代谢疾病。尽管存在各种定义MetSyn的标准，但疾病条件包括腹型肥胖、胰岛素抵抗、血清甘油三酯水平升高、血清高密度脂蛋白(HDL)水平下降、血糖水平升高和高血压。随着肥胖成为全球流行病，MetSyn的发病率预计将增加。这一增加可能会产生不利影响，实际上可能会扭转美国心血管疾病减少的趋势。最近的全基因组关联研究已经确定了400多个与肥胖、糖尿病、心血管疾病和心脏代谢特征相关的基因组基因座。然而，大多数潜在的基因和这些基因如何在疾病过程中起作用的相关机制仍不清楚。这项建议概述了一种综合的系统遗传学方法，通过结合分别属于男性代谢综合征(METSIM)和杂交小鼠多样性小组(HMDP)研究的广泛表型的人类和小鼠队列的数据，确定GWAS基因座下的因果基因和途径。它还概述了Mete Civelek博士广泛的职业发展计划，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K99奖项阶段，PI将使用表达阵列和来自人类受试者的下一代图谱来测量脂肪mRNA和microRNA的丰度，并将使用高密度SNP阵列进行基因分型。类似的测量也将在小鼠身上进行。GWAS基因座上显著的基因型-表达特征关联将被用来预测与疾病发展相关的基因。共表达网络将从表达数据中构建，并将用于预测因果基因与已知途径的关系。在预测了K99奖项阶段的因果基因及其功能后，PI将在奖项的R00阶段使用体外和体内实验来测试这些预测。初步结果证实，编码RNA结合蛋白的CPEB4基因是人类5号染色体座位上影响腰臀比的重要关联信号的原因基因。离体 研究和生物信息学方法将确定这种RNA结合蛋白靶向的mRNAs。利用脂肪细胞特异性CPEB4转基因和基因敲除小鼠进行的活体研究将确定它在调节脂肪质量和相关代谢特征方面的作用。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，导致对基因网络的机械理解，这些基因网络受到导致心脏代谢性疾病的疾病相关遗传变异的干扰。

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.