Genetic Background of Metabolic Syndrome-Related Traits

项目总结（见说明）： 以往的流行病学研究表明，代谢综合征是非常常见的人群患病率约30%的中年美国人。代谢综合征易导致冠状动脉疾病，冠状动脉疾病是美国人死亡的主要原因。血浆甘油三酯（TG）升高和高密度脂蛋白胆固醇（HDL-C）降低是代谢综合征的关键致动脉粥样硬化脂质表型。 然而，代谢综合征的遗传基础还不清楚。项目2的主要目标是系统地鉴定与代谢综合征的脂质性状（TG和HDL-C）相关的DNA序列变异、基因和代谢途径，并研究序列变异在人群中的风险以及基因-基因和基因-环境相互作用。具体的爱米侧重于重新测序的基因，我们确定在本项目2（WWOX和LMFI）的前一个周期，以确定表现出最强的表型效应的变体。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的生物标志物和靶点。 Specific Aim 2整合了从小鼠和人类获得的基因组数据，以系统地鉴定在人类代谢综合征相关脂质性状的DNA和RNA水平上涉及的新基因和途径。 由于个体发生复杂心血管表型的风险是易变性变体、环境因素、行为和机会的组合，因此我们将在一个大型人群样本中调查由多条证据支持的DNA序列变体，以及基因-基因和基因-环境相互作用，男性代谢综合征（METSIM）研究，目前包括8，600名芬兰人，最终在2010年有一万名芬兰人。本研究将与芬兰库奥皮奥大学的Markku Laakso博士合作进行，他正在收集METSIM样本。利用这一广泛的人群样本以及可用于研究的精确表型，为我们提供了探索人群风险和基因与环境相互作用的独特机会。基因-环境互作是复杂性状表达的关键因素，但在目前的全基因组关联研究中，由于缺乏像METSIM研究那样具有足够精确表型信息的群体样本，基因-环境互作分析还没有得到充分的研究。阐明影响人类代谢综合征高易感性的未知遗传因素和分子机制对美国的医疗保健体系具有重要意义。

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.