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: 8284396
• 负责人: Paivi Pajukanta
• 金额: $ 69.47万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284396
• 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; 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. 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.

描述（由申请人提供）：冠状动脉疾病（CAD）是世界范围内死亡和死亡的头号原因。高水平的血清甘油三酯（TG）和低水平的血清高密度脂蛋白胆固醇（HDL-C）是CAD的主要危险因素。以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，高血清TG和低HDL-C的遗传因素研究不足，识别不佳。由于墨西哥裔美国人和遗传相关的拉丁美洲人口代表了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的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）正在成为识别新风险变异的首选方法。然而，迄今为止，墨西哥人口在这些GWAS中没有代表性。此外，没有关于全基因组连锁不平衡（LD）结构的信息是在墨西哥人，因为公开的HapMap数据不能直接应用于混合墨西哥人口的后裔，最近的混合美洲印第安人和欧洲血统与非洲血统的一小部分。本申请的主要目的是使用在INCMNSZ收集的4400例墨西哥高甘油三酯血症病例和对照以及一项具有41，207名受试者的大型墨西哥基于人口的全国调查，鉴定形成墨西哥人对血清TG水平升高的高遗传易感性和相关致动脉粥样硬化代谢性状如低HDL-C的DNA序列变体。2000年由墨西哥公共卫生研究所作为全国调查样本收集。我们建议在墨西哥高TG病例和对照中分两个阶段进行GWAS（具体目标1）。来自50名墨西哥高血脂症受试者和50名正常血脂症受试者的脂肪活检的基因表达数据将用作额外的筛选器，以选择GWAS第2阶段的DNA变体。在具体目标2中，我们建议在41，207名墨西哥人的群体水平上研究GWAS中确定为风险，基因-基因和基因-环境相互作用的重要变异。虽然特定目标1-2旨在识别常见的DNA变异，但在特定目标3中，我们建议通过对墨西哥人中与高TG相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。实现这些特定目标应该有助于我们识别使墨西哥人易患高TG的易感性变体。 公共卫生相关性：墨西哥人口有高倾向血清甘油三酯升高。然而，这种易感性增加的遗传因素研究不足，鉴定不佳。本申请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，并确定与墨西哥大型基于人群的全国调查中确定的变异相关的人群风险。