Genetics of high serum triglycerides and related metabolic traits in Mexicans

描述（由申请人提供）：冠状动脉疾病（CAD）是世界范围内导致死亡和死亡的头号原因。高水平的血清甘油三酯（TGs）和低水平的血清高密度脂蛋白胆固醇（HDL-C）是冠心病的主要危险因素。以前的流行病学研究表明，这两种脂质紊乱是墨西哥人最常见的两种血脂异常。然而，墨西哥人高血清TGs和低HDL-C的遗传因素尚未得到充分研究和鉴定。由于墨西哥裔美国人和遗传相关的拉丁美洲人口是美国增长最快的少数民族，阐明影响墨西哥人对这些常见血脂异常易感性增加的未知遗传因素对这些美国少数民族和美国医疗保健系统具有重要意义。复杂心血管特征的全基因组关联研究（GWAS）正成为鉴定新型风险变异的首选方法。然而，到目前为止，在这些GWAS中还没有墨西哥人口的代表。此外，没有关于墨西哥人全基因组连锁不平衡（LD）结构的信息，因为公开可用的HapMap数据不能直接应用于最近由美洲印第安人和欧洲血统与一小部分非洲血统混合而成的墨西哥混合人口。本应用程序的主要目标是利用INCMNSZ收集的4400名墨西哥高甘油三酯血症病例和对照，以及墨西哥公共卫生研究所于2000年收集的41207名受试者作为全国调查样本，确定形成墨西哥人血清TG水平升高和相关动脉粥样硬化代谢特征（如低HDL-C）的高遗传易感性的DNA序列变异。我们建议在墨西哥高TG病例和对照组中分两个阶段进行GWAS（具体目标1）。来自50名墨西哥高甘油三酯血症患者和50名正常血脂患者的脂肪活检的基因表达数据将被用作额外的过滤器，以选择GWAS第二阶段的DNA变体。在具体目标2中，我们建议在41,207名墨西哥人的人群水平上调查在GWAS中被认为具有显著风险、基因-基因和基因-环境相互作用的变异。虽然Specific Aims 1-2的目标是鉴定常见的DNA变异，但在Specific Aim 3中，我们建议通过对墨西哥人高TGs相关基因的广泛重测序来鉴定所有现有的罕见变异。完成这些具体目标将有助于我们确定易患墨西哥人高TGs的易感性变异。公共卫生相关性：墨西哥人口具有血清甘油三酯升高的高易感性。然而，导致这种易感性增加的遗传因素尚未得到充分调查和鉴定。本应用程序的主要目标是在墨西哥人中进行全基因组关联研究，以确定高血清甘油三酯的DNA序列变异，并在墨西哥以人口为基础的大型国家调查中确定与已确定变异相关的人口风险。

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) is the number one cause of death and mortality world-wide. High levels of serum triglycerides (TGs) and low levels of serum high-density lipoprotein cholesterol (HDL-C) are major risk factors for CAD. Previous epidemiological studies have shown that these two lipid disturbances are the two most common dyslipidemias in Mexicans. However, the genetic factors underlying high serum TGs and low HDL-C are underinvestigated and poorly identified in Mexicans. As the Mexican-American and the genetically related Latin-American populations represent the fastest growing minority in the United States, elucidation of the unknown genetic factors influencing the increased susceptibility of Mexicans to these common dyslipidemias is of great relevance to these U.S. minorities and the American healthcare system. Genome-wide association studies (GWAS) of complex cardiovascular traits are becoming the method of choice to identify novel risk variants. However, the Mexican population has thus far not been represented among these GWAS. Furthermore, no information about genome-wide linkage disequilibrium (LD) structure is available in Mexicans, as the publicly available HapMap data cannot be directly applied for the admixed Mexican population descended from a recent mix of Amerindian and European ancestry with a small proportion of African ancestry. The major goal of this application is to identify the DNA sequence variants that form the high genetic predisposition of Mexicans to elevated serum TG levels and related atherogenic metabolic traits such as low HDL-C using 4400 Mexican hypertriglyceridemic cases and controls, collected at the INCMNSZ, and a large Mexican population-based national survey with 41,207 subjects, collected in 2000 as the National Survey sample by the Institute for Public Health of Mexico. We propose to perform a GWAS in Mexican high TG cases and controls in two stages (Specific Aim 1). Gene expression data from fat biopsies from 50 Mexican subjects with hypertriglyceridemia and 50 with normolipidemia will be utilized as an additional filter to select DNA variants for stage 2 of the GWAS. In Specific Aim 2, we propose to investigate the variants identified as significant in the GWAS for risk, gene-gene and gene-environment interactions at the population level in 41,207 Mexicans. While Specific Aims 1-2 are targeted to identify common DNA variants, in Specific Aim 3 we propose to identify all existing rare variants by extensive resequencing of the genes implicated for high TGs in Mexicans. Accomplishing these Specific Aims should help us identify the susceptibility variants predisposing the Mexicans for high TGs. PUBLIC HEALTH RELEVANCE: The Mexican population has a high predisposition to elevated serum triglycerides. However, the genetic factors underlying this increased susceptibility are underinvestigated and poorly identified. The major goal of this application is to perform a genome-wide association study in Mexicans to identify DNA sequence variants for high serum triglycerides and to determine the population risks related to the identified variants in a large Mexican population-based national survey.