Systems genetics analysis of cardiometabolic trait loci in humans

人类心脏代谢特征位点的系统遗传学分析

• 批准号: 9171602
• 负责人: Mete Civelek
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171602
• 关键词: 5q35.2; Adipocytes; Adipose tissue; Affect; Award; Binding; Bioinformatics; Biological Preservation; Blood Glucose; Body fat; Cardiovascular Diseases; Cardiovascular system; Central obesity; Chromosomes; Chromosomes, Human, Pair 5; Clinical; Complex; Computer Simulation; Data; Depressed mood; Development; Development Plans; Diabetes Mellitus; Diagnosis; Disease; Environmental Risk Factor; Epidemic; Fatty acid glycerol esters; Foundations; Functional disorder; Gene Chips; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Goals; Health; High Density Lipoproteins; Human; Human Genome; Hybrids; Hypertension; In Vitro; Inbred Strains Mice; Incidence; Inflammatory; Insulin Resistance; Knock-out; Knockout Mice; Measurement; Measures; Mentorship; Messenger RNA; Metabolic; Metabolic syndrome; MicroRNAs; Molecular; Molecular Analysis; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Pathway interactions; Phase; Phenotype; Play; Polyadenylation; Positioning Attribute; Process; Quality Control; Quantitative Trait Loci; RNA-Binding Proteins; Regulation; Research; Resources; Role; Sampling; Serum; Signal Transduction; Single Nucleotide Polymorphism; Solid; System; Systems Biology; Testing; Tissues; Transcript; Transgenic Mice; Transgenic Organisms; Translations; Triglycerides; Waist-Hip Ratio; career development; cohort; density; disorder prevention; disorder risk; genetic analysis; genetic approach; genetic variant; genome wide association study; human subject; in vivo; men; next generation; novel; population based; post-doctoral training; programs; research study; subcutaneous; trait; trend

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.

描述（由申请人提供）：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。虽然存在各种定义MetSyn的标准，但疾病条件包括腹部肥胖、胰岛素抵抗、血清甘油三酯水平升高、血清高密度脂蛋白（HDL）水平降低、血糖水平升高和高血压。随着肥胖成为一种世界性的流行病，MetSyn的发病率预计会增加。这种增加可能会产生有害影响，实际上可能会逆转美国心血管疾病减少的趋势。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、心血管疾病和心脏代谢特征相关的基因组位点。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，分别作为男性代谢综合征（METSIM）和杂交小鼠多样性小组（HMDP）研究的一部分，确定GWAS位点的因果基因和通路。它还概述了一个广泛的职业发展计划，为Mete Civelek博士完成博士后培训博士的指导下，Aldons Lusis和过渡到一个独立的学术地位，建立心血管病理生理学的多学科研究计划。在K99阶段，PI将使用表达阵列测量脂肪mRNA和microRNA的丰度，并使用高密度SNP阵列对人类受试者进行下一代分析。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性状关联将用于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。在奖励的K99阶段预测了因果基因及其功能之后，PI将在奖励的R00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CPEB4是人类腰臀比5号染色体位点上重要关联信号的致病基因。在体外