Systems genetics analysis of cardiometabolic trait loci in humans

项目总结 代谢综合征(MetSyn)是一组共同发生并促进 发生心血管疾病(CVD)和2型糖尿病。尽管定义的各种标准 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(高密度脂蛋白)水平降低、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。这一增长 可能会有有害的影响，实际上可能会扭转美国心血管疾病减少的趋势。近期 全基因组关联研究(GWAS)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。然而，大多数潜在的基因和相关的 这些基因座如何在疾病过程中起作用的机制尚不清楚。 这项建议概述了一种综合的系统遗传学方法，以确定因果基因和途径。 通过结合来自广泛表型的人类和小鼠队列的数据来揭示Gwas基因座的基础 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， 分别进行了分析。它还概述了梅特·西维莱克博士要完成的广泛的职业发展计划 在Aldons Lusis博士的指导下进行博士后培训并过渡到独立学者 在心血管病理生理学方面建立多学科研究计划的职位。 在奖项的K99阶段，PI将使用以下方法测量脂肪mRNA和microRNA丰度 将使用HIGH进行基因分型的人类受试者的表达阵列和下一代图谱 密度SNP阵列。类似的测量也将在小鼠身上进行。显著的基因表达性状 GWAS基因座的关联性将被用来预测与疾病发展相关的基因。共同-- 表达网络将从表达数据中构建，并将用于预测 具有已知途径的因果基因。预测了K99期间的致病基因及其功能 在颁奖阶段，PI将在R00期间使用体外和体内实验来测试这些预测 颁奖阶段。初步结果表明，编码RNA结合蛋白的CPEB4是 5号染色体座位上影响腰臀比显著关联信号的原因基因 人类。体外研究和生物信息学方法将确定该RNA靶向的mRNAs 结合蛋白。利用脂肪细胞特异性CPEB4转基因和基因敲除小鼠进行的体内研究将确定其 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将系统生物学和分子分析结合在一起 体外和体内实验，导致了对基因网络的机械理解 通过与疾病相关的基因变异导致心脏代谢障碍。

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.