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）是一组同时发生并促进心血管疾病（CVD）和2型糖尿病发展的代谢病症。尽管存在多种定义 MetSyn 的标准，但疾病状况包括腹部肥胖、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。随着肥胖已成为全球流行病，MetSyn 的发病率预计将会增加。这种增加可能会产生有害影响，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 (GWAS) 已识别出 400 多个与肥胖、糖尿病、CVD 和心脏代谢特征相关的基因组位点。然而，大多数潜在基因以及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，通过结合男性代谢综合征 (METSIM) 和混合小鼠多样性小组 (HMDP) 研究的一部分的广泛表型人类和小鼠群体的数据，来识别 GWAS 位点背后的因果基因和途径，分别。它还概述了 Mete Civelek 博士的广泛职业发展计划，以在 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项目过渡到独立的学术职位。 在奖励的 K99 阶段，PI 将使用表达阵列和下一代分析来测量人类受试者的脂肪 mRNA 和 microRNA 丰度，这些人类受试者将使用高密度 SNP 阵列进行基因分型。类似的测量将在小鼠中进行。 GWAS 位点的显着基因型表达性状关联将用于预测与疾病发展相关的基因。共表达网络将根据表达数据构建，并将用于预测因果基因与已知途径的关系。在奖励的 K99 阶段预测了因果基因及其功能后，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。初步结果已确定编码 RNA 结合蛋白的 CPEB4 是人类腰臀比 5 号染色体位点中显着关联信号的致病基因。体外 研究和生物信息学方法将鉴定该 RNA 结合蛋白靶向的 mRNA。使用脂肪细胞特异性 Cpeb4 转基因和敲除小鼠的体内研究将确定其在调节脂肪量和相关代谢特征中的作用。 拟议研究的总体目标是将系统生物学和分子分析整合到体外和体内实验中，从而从机制上理解基因网络，这些基因网络受到导致心脏代谢紊乱的疾病相关遗传变异的干扰。