Identification of genetic variants influencing plasma lipid levels in the population isolate of Kosrae by whole genome approaches and characterization of their functional role in metabolism

血脂异常是动脉粥样硬化性心血管疾病的主要危险因素，动脉粥样硬化性心血管疾病是当今工业化国家发病率和死亡率的主要原因。对常见形式的血脂异常的易感性遵循复杂的遗传特征，并取决于多个基因和环境影响之间的相互作用。我们的知识的多基因背景的各种形式的常见血脂异常仍然是有限的。全基因组关联研究为发现此类复杂性状的基因提供了一种很有前途的方法。本提案的目的是使用全基因组方法，鉴定影响科斯雷岛（密克罗尼西亚联邦）分离人群脂质表型的遗传变异。血脂异常以及心血管疾病的其他代谢危险因素在这一人群中是地方性的，由于遗传复杂性降低，其分离为此类遗传研究提供了理想的环境。目前正在对3212名岛民进行50万SNP阵列的全基因组扫描。将应用基于家族的关联检验来确定与血浆脂质和脂蛋白水平相关的SNP。将进行高密度SNP作图、单倍型分析和重测序以鉴定致病基因。最后，将测试它们与其他人群中疾病表型的关联，以及它们在体外和体内脂质途径中的功能意义。拟议项目的预期结果将引起对分子基础的更好理解，以及在预防动脉粥样硬化性血脂异常方面开发新的诊断和治疗策略。

Dyslipidemia is a primary risk factor for atherosclerotic cardiovascular disease, the major cause of morbidity and mortality in the industrialized countries today. Susceptibility to common forms of dyslipidemias follows complex genetic traits and is dependent upon interactions between multiple genes and environmental influences. Our knowledge about the polygenetic background of the various forms of common dyslipidemias is still limited. Genome wide association studies represent a promising approach for gene discovery in such complex traits. The aim of this proposal is to identify genetic variants influencing lipid phenotypes in the isolate population of the island of Kosrae (Federated States of Micronesia), using a whole genome approach. Dyslipidemia, as well as other metabolic risk factors for cardiovascular disease are endemic in this population and its isolation provides an ideal setting for such genetic studies, because of reduced genetic complexity. A whole genome scan with 500k SNP arrays is currently being performed on 3212 islanders. Family based association testing will be applied to determine SNPs associated with plasma lipid and lipoprotein levels. High-density SNP mapping, haplotype analysis and resequencing will be conducted to identify the causative genes. Finally, their association with disease phenotypes in other populations, as well as their functional significance in lipid pathways both in vitro and in vivo will be tested. The expected results of the proposed project will give rise to a better understanding of the molecular basis, as well as the development of novel diagnostic and therapeutic strategies in the prevention of atherogenic dyslipidemias.