Genetic Background of Metabolic Syndrome-Related Traits

代谢综合征相关特征的遗传背景

• 批准号: 8001172
• 负责人: Paivi Pajukanta
• 金额: $ 43.56万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001172
• 关键词: American; Behavior; Biological Markers; Cardiovascular system; Cause of Death; Clinical; Collaborations; Complex; Coronary Arteriosclerosis; DNA; DNA Resequencing; DNA Sequence; Data; Dyslipidemias; Environment; Environmental Risk Factor; Epidemiologic Studies; Exhibits; Finland; Frequencies; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genets; Genomics; Goals; Healthcare Systems; High Density Lipoprotein Cholesterol; Human; Hypertension; Hypertriglyceridemia; Individual; Instruction; Insulin Resistance; Intervention; Lipase; Lipids; Metabolic Pathway; Metabolic syndrome; Molecular; Mus; Nature; Obesity; Oxidoreductase; Oxidoreductase Gene; Pathway interactions; Phenotype; Plasma; Population; Populations at Risk; Predisposition; Prevalence; RNA; Research Personnel; Risk; Sampling; Serum; Tail; Triglycerides; Universities; Variant; base; cohort; gene environment interaction; genome wide association study; men; middle age; novel; population based; trait

PROJECT SUMMARY (See instructions): Previous epidemiological studies have shown that the metabolic syndrome is very common with a population prevalence of ~30% in middle-aged Americans. The metabolic syndrome predisposes to coronary artery disease, the major cause of death in the U.S. Elevated plasma triglycerides (TGs) and low high-density lipoprotein cholesterol (HDL-C) are the key atherogenic lipid phenotypes ofthe metabolic syndrome. However, the genetic basis for the metabolic syndrome is not well understood. The major goal of project 2 is to systematically identify DNA sequence variants, genes and metabolic pathways contributing to the lipid traits, TGs and HDL-C, of the metabolic syndrome and to investigate the sequence variants for risk as well as for gene-gene and gene-environment interacfions in the populafion. Specific Aimi focuses on resequencing ofthe genes we identified during the previous cycle of this Project 2 (WWOX and LMFI) to identify the variants exhibiting the strongest phenotypic effects. These variants will be further investigated in functional studies. Our ultimate goal is to provide novel biomarkers and targets for clinical interventions. Specific Aim 2 integrates genomic data obtained from mouse and human to systemically identify novel genes and pathways implicated at the DNA and RNA level in the metabolic syndrome related lipid traits in human. As an individual's risk to develop a complex cardiovascular phenotype is a combination of suscepfibility variants, environmental factors, behavior and chance, we will investigate the DNA sequence variants supported by multiple lines of evidence for risk as well as for gene-gene and gene-environment interactions in a large populafion sample, the METabolic Syndrome In Men (METSIM) study, comprising currenfiy 8,600 Finns, and ultimately 10,000 Finns in 2010. This study will be performed in collaboration with Dr. Markku Laakso, University of Kuopio, Finland who is collecfing the METSIM sample. Ufilizing this extensive population sample with refined phenotypes available for the study gives us a unique opportunity to explore the population risks and gene-environment interactions. The gene-environment interactions, critical for the expression of complex traits, have not been investigated in the r;ecent genome-wide association studies, because there are very few large enough population samples such as the METSIM study with refined enough phenotypic informafion available for gene-environment interaction analyses. Elucidafion of the unknown genefic factors and molecular mechanisms influencing the high suscepfibility to the metabolic syndrome in human is of great relevance to the American healthcare system.

项目摘要（请参阅说明）： 先前的流行病学研究表明，中年美国人的人口患病率约为30％，代谢综合征非常普遍。代谢综合征易感冠状动脉疾病，美国的主要死亡原因升高血浆甘油三酸酯（TGS）和低密度脂蛋白胆固醇（HDL-C）是代谢综合征的关键动脉粥样硬化脂质表型。 但是，代谢综合征的遗传基础尚不清楚。项目2的主要目的是系统地识别代谢综合征的脂质性状，TGS和HDL-C的DNA序列变异，基因和代谢途径，并研究风险的序列变体，以及基因基因和基因 - 基因和基因之间的群体中的群体。特定的Aimi专注于在该项目2的上一个周期（WWOX和LMFI）上确定的基因重新方程，以识别表现出最强表型效应的变体。这些变体将在功能研究中进一步研究。我们的最终目标是为临床干预提供新颖的生物标志物和靶标。 具体目标2整合了从小鼠和人类获得的基因组数据，以系统地识别与人类代谢综合征相关的脂质性状中与DNA和RNA水平有关的新型基因和途径。 As an individual's risk to develop a complex cardiovascular phenotype is a combination of suscepfibility variants, environmental factors, behavior and chance, we will investigate the DNA sequence variants supported by multiple lines of evidence for risk as well as for gene-gene and gene-environment interactions in a large populafion sample, the METabolic Syndrome In Men (METSIM) study, comprising currenfiy 8,600 Finns,最终在2010年最终将有10,000份芬兰人。这项研究将与芬兰Kuopio大学的Markku Laakso博士合作进行，他正在与MetSim样本一起进行。通过可用于研究的精制表型来使这一广泛的人群样本为我们提供了一个独特的机会，可以探索人口风险和基因环境相互作用。在R; ECENT ACENT基因组关联研究中尚未研究基因环境相互作用，对于复杂性状的表达至关重要，因为很少有足够大的人群样本，例如具有足够精制的表型信息的METSIM研究，可用于基因环境相互作用分析。未知基因的因素和分子机制影响了人类代谢综合征的高可疑性与美国医疗保健系统非常相关。