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: 7572443
• 负责人: Paivi Pajukanta
• 金额: $ 73.74万
• 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/7572443
• 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; 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; 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; public health relevance; 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）是全球死亡和死亡率的第一大原因。高水平的血清甘油三酸酯（TGS）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。先前的流行病学研究表明，这两种脂质障碍是墨西哥人最常见的血脂异常。然而，在墨西哥人中，高血清TGS和低HDL-C的遗传因素缺乏评估，并且鉴定不足。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群体，因此阐明了未知的遗传因素影响墨西哥人对这些常见血脂异性疾病的易感性提高与这些美国少数民族和美国医疗系统的敏感性很大。复杂心血管特征的全基因组关联研究（GWAS）已成为确定新型风险变异的首选方法。但是，到目前为止，墨西哥人口尚未在这些GWA中得到代表。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，因为公开可用的HAPMAP数据不能直接用于墨西哥近期墨西哥人口，而不是最近与非洲祖先的少量组合在一起。该应用的主要目的是确定墨西哥人对较高遗传性易感性的变异，这些变异使用4400墨西哥人的高度甘油三酸酯病例和对照组，在INCMNSZ中收集的2000年度调查量41，207墨西哥公共卫生研究所。我们建议在墨西哥高的TG病例中进行GWAS，并在两个阶段进行对照（特定AIM 1）。来自50名墨西哥受试者患有高甘油三酯血症和50例正常血症血症的脂肪活检的基因表达数据将被用作GWAS第2期的DNA变体的附加过滤器。在特定目标2中，我们建议研究在41,207墨西哥人的人口水平上的风险，基因 - 基因和基因环境相互作用中被确定为重要的变体。虽然特定目标1-2旨在识别常见的DNA变异，但在特定的目标3中，我们建议通过广泛重新定制与墨西哥人高TGS有关的基因来识别所有现有的稀有变体。实现这些特定目标应该有助于我们确定易感墨西哥人对高TG的敏感性变体。 公共卫生相关性：墨西哥人口对升高的血清甘油三酸酯具有很高的倾向。但是，这种增加的敏感性的遗传因素缺乏评估且鉴定不佳。该应用的主要目的是在墨西哥人进行全基因组关联研究，以鉴定高血清甘油三酸酯的DNA序列变体，并确定与墨西哥大型墨西哥人口的大型国家调查中与已确定变体有关的人群风险。