Genetic susceptibility to Common Lipid Disorders in Mexico

墨西哥常见脂质疾病的遗传易感性

• 批准号: 7440183
• 负责人: Paivi Pajukanta
• 金额: $ 34.94万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7440183
• 关键词: 10q; 16q; 20q; American; Apolipoproteins B; Atherosclerosis; Candidate Disease Gene; Caucasians; Caucasoid Race; Cause of Death; Cholesterol; Chromosomes; Cities; Collaborations; Coronary heart disease; DNA; DNA Sequence; Data; Diabetes Mellitus; Disease; Dyslipidemias; Familial Combined Hyperlipidemia; Family; Genes; Genetic; Genetic Predisposition to Disease; Genome Scan; Healthcare Systems; Hepatic; High Density Lipoprotein Cholesterol; Hyperlipidemia; Institutes; International; Investigation; Link; Lipids; Los Angeles; Mexican; Mexican Americans; Mexico; Minority; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Pilot Projects; Platelet Factor 4; Population; Predisposition; Prevalence; Publishing; Research Personnel; Risk Factors; Role; Serum; Susceptibility Gene; Time; Triglycerides; United States; Variant; genetic variant; genome wide association study; lipid disorder; novel; programs; rapid growth; trait; transcription factor USF

DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is the leading cause of death in both the U.S and Mexico. Unfavorable serum lipid levels, such as high serum total cholesterol, high serum triglycerides and low high-density lipoprotein cholesterol, are well-known risk factors for CHD. Although several studies have demonstrated that the Mexican population has an increased predisposition to dyslipidemias, this population is underinvestigated for the genetic factors conferring this susceptibility. Considering the rapid growth of the Mexican-American population in the U.S., investigation of these genetic factors in the Mexican population is of great importance and relevant also to this U.S. minority. To identify genetic variants that confer susceptibility to high serum lipid levels in Mexicans, we recently began an international collaboration between investigators at UCLA, Los Angeles, and Institute Nacional de Ciencias Medicas y Nutricion, Mexico City. We examined 24 extended Mexican familial combined hyperlipidemia (FCHL) families for one gene and seven chromosomal loci previously detected for FCHL in Caucasian families. FCHL is the most common mixed dyslipidemia predisposing to CHD, with an estimated prevalence of 8% in Mexicans. We demonstrated that the upstream transcription factor 1 (USF1) gene and chromosomal loci on 10q and 16q are implicated in the Mexican FCHL families (Huertas-Vazquez et al. 2005). This study is the first one to extensively investigate the genetic component of the FCHL disorder in Mexicans. Recently, we also identified significant associations between DMA variants in the hepatic nuclear factor 4, alpha (HNF4A) gene and FCHL in Mexicans. Although HNF4A variants have previously been associated with type 2 diabetes mellitus (T2DM), our data show for the first time that the HNF4A variants are associated with serum lipid levels. Considering the clear phenotypic overlap between T2DM and FCHL, we hypothesize that HNF4A is a good candidate gene for FCHL as weJI. We propose to identify novel susceptibility loci for common lipid disorders in Mexicans and further examine these implicated genes. In Specific Aim 1, we will perform a genome scan in Mexican FCHL families to identify additional susceptibility loci undiscovered or nonexistent in the previously studied Caucasian populations. In Specific Aim 2, we will investigate USF1, HNF4A and the chromosomal loci implicated in the genome scan to characterize the DNA variants conferring the susceptibility to FCHL in Mexicans.

描述（由申请人提供）：冠心病 (CHD) 是美国和墨西哥的主要原因。不利的血脂水平，例如高血清总胆固醇、高血清甘油三酯和低高密度脂蛋白胆固醇，是众所周知的冠心病危险因素。尽管多项研究表明墨西哥人群更容易患血脂异常，但对该人群造成这种易感性的遗传因素的调查还不够。考虑到美国墨西哥裔美国人人口的快速增长，对墨西哥人口中这些遗传因素的研究非常重要，并且与这个美国少数民族相关。为了确定墨西哥人对高血脂水平易感性的遗传变异，我们最近开始了洛杉矶加州大学洛杉矶分校和墨西哥城国家医学与营养研究所的研究人员之间的国际合作。我们检查了 24 个墨西哥家族性混合性高脂血症 (FCHL) 家族的一个基因和七个染色体位点，这些基因座先前在白种人家族中检测到 FCHL。 FCHL 是最常见的混合性血脂异常，易诱发冠心病，估计墨西哥人的患病率为 8%。我们证明上游转录因子 1 (USF1) 基因以及 10q 和 16q 上的染色体位点与墨西哥 FCHL 家族有关（Huertas-Vazquez 等，2005）。这项研究是第一个广泛研究墨西哥人 FCHL 疾病遗传成分的研究。最近，我们还发现墨西哥人肝核因子 4、α (HNF4A) 基因的 DMA 变异与 FCHL 之间存在显着关联。尽管 HNF4A 变异体之前已被认为与 2 型糖尿病 (T2DM) 有关，但我们的数据首次显示 HNF4A 变异体与血清脂质水平相关。考虑到 T2DM 和 FCHL 之间明显的表型重叠，我们假设 HNF4A 是 FCHL 的一个很好的候选基因，如 weJI。我们建议确定墨西哥人常见脂质疾病的新易感性位点，并进一步检查这些相关基因。在具体目标 1 中，我们将对墨西哥 FCHL 家族进行基因组扫描，以确定先前研究的白种人群体中未发现或不存在的其他易感位点。在具体目标 2 中，我们将研究 USF1、HNF4A 和基因组扫描中涉及的染色体位点，以表征墨西哥人对 FCHL 易感性的 DNA 变异。