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，代谢综合征非常常见，在美国中年人群中的患病率约为30%。代谢综合征易患冠状动脉疾病，冠心病是美国人的主要死亡原因。血浆甘油三酯(TGS)升高和高密度脂蛋白胆固醇(HDL-C)降低是代谢综合征致动脉粥样硬化的关键脂质表型。 然而，代谢综合征的遗传基础还不是很清楚。项目2的主要目标是系统地识别导致代谢综合征的脂肪性状TGS和高密度脂蛋白-C的DNA序列变异、基因和代谢途径，并研究在人群中风险以及基因-基因和基因-环境相互作用的序列变异。具体目标1侧重于对我们在本项目2的前一个周期(WWOX和LMFI)中确定的基因进行重新测序，以确定表现出最强表型效应的变体。这些变异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记物和靶点。 特异性目标2整合从小鼠和人类获得的基因组数据，系统地识别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新途径。 由于个体患复杂心血管表型的风险是易感变异、环境因素、行为和机会的组合，我们将在一个大的人群样本中研究DNA序列变异，并研究基因-基因和基因-环境相互作用的风险以及基因-基因和基因-环境交互作用。该研究目前有8,600名芬兰人参与，2010年最终有10,000名芬兰人参与。这项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。利用这一可用于研究的具有精炼表型的广泛人口样本，为我们提供了一个独特的机会来探索人口风险和基因-环境相互作用。在最近的全基因组关联研究中，对复杂性状表达至关重要的基因-环境互作还没有得到研究，因为很少有足够大的群体样本，如METSIM研究，可以提供足够精确的表型信息来进行基因-环境互作分析。阐明影响人类对代谢综合征高度易感性的未知遗传因素和分子机制，对美国医疗保健系统具有重要意义。

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 interactions in the population. Specific Aim 1 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 susceptibility 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 population sample, the METabolic Syndrome In Men (METSIM) study, comprising currently 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 collecting the METSIM sample. Utilizing 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 recent genome-wide association studies, because there are very few large enough population samples such as the METSIM study with refined enough phenotypic information available for gene-environment interaction analyses. Elucidation of the unknown genetic factors and molecular mechanisms influencing the high susceptibility to the metabolic syndrome in human is of great relevance to the American healthcare system.