Genetics of high serum triglycerides and related metabolic traits in Mexicans

墨西哥人高血清甘油三酯的遗传学及相关代谢特征

• 批准号: 8460151
• 负责人: Paivi Pajukanta
• 金额: $ 59.15万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460151
• 关键词: African; American; Amerindian; Biopsy; California; Cantor; Cardiovascular system; Cause of Death; Chairperson; Chronic Disease; Complex; Coronary Arteriosclerosis; DNA; DNA Resequencing; DNA Sequence; Data; Doctor of Philosophy; Dyslipidemias; Endocrinology; Epidemiologic Studies; European; Fatty acid glycerol esters; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Head; Health; Healthcare Systems; High Density Lipoprotein Cholesterol; Human Genetics; Hypertriglyceridemia; Informed Consent; Institutes; Linkage Disequilibrium; Lipids; Los Angeles; Medical; Medicine; Metabolic; Methods; Mexican; Mexican Americans; Mexico; Minority; Molecular Biology; Morbidity - disease rate; Participant; Phenotype; Population; Predisposition; Principal Investigator; Public Health; Publishing; Research; Research Personnel; Resources; Risk; Risk Factors; Salinum; Sampling; Science; Serum; Staging; Structure; Surveys; Triglycerides; United States; Universities; Variant; case control; gene environment interaction; genome wide association study; genome-wide; genome-wide linkage; interest; mortality; novel; population based; population health; professor; risk variant; trait; web site

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.

描述(申请人提供)：冠状动脉疾病(CAD)是世界范围内死亡和死亡的头号原因。血清甘油三酯(TGS)水平高和血清高密度脂蛋白胆固醇(HDLC)水平低是冠心病的主要危险因素。先前的流行病学研究表明，这两种血脂紊乱是墨西哥人最常见的两种血脂异常。然而，在墨西哥人中，导致高血清TGS和低高密度脂蛋白-C的遗传因素还没有得到充分的研究和识别。由于墨西哥裔美国人和基因相关的拉丁美洲人是美国增长最快的少数群体，澄清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，对这些美国少数族裔和美国医疗体系具有重要意义。对复杂心血管特征的全基因组关联研究(GWAS)正成为识别新的风险变异的首选方法。然而，到目前为止，墨西哥人口还没有在这些全球妇女中占有一席之地。此外，墨西哥人没有关于全基因组连锁不平衡(LD)结构的信息，因为公开的HapMap数据不能直接应用于最近混合了美洲印第安人和欧洲人后裔的墨西哥人，其中有一小部分非洲人的祖先。这项应用的主要目标是利用INCMNSZ收集的4400例墨西哥高甘油三酯血症病例和对照以及2000年墨西哥公共卫生研究所作为全国调查样本收集的41,207名墨西哥人的全国调查样本，识别形成墨西哥人对血清甘油三酯水平升高和相关的致动脉粥样硬化代谢特征的高遗传易感性的DNA序列变异。我们建议在墨西哥高甘油三酯患者和对照中分两个阶段进行GWA(特定目标1)。来自50名患有高甘油三酯血症和50名正常血脂的墨西哥受试者的脂肪活检的基因表达数据将被用作额外的筛选器，以选择第二阶段的DNA变异体。在具体目标2中，我们建议在41,207名墨西哥人中，在人群水平上调查被确定为对风险、基因-基因和基因-环境相互作用有显著影响的变异。虽然特定目标1-2的目标是识别常见的DNA变异，但在特定目标3中，我们建议通过对与墨西哥人高TGS有关的基因进行广泛的重新测序来识别所有现有的罕见变异。实现这些特定的目标应该有助于我们识别导致墨西哥人高TGS的易感变异。