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: 7656874
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656874
• 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; Disease; Dyslipidemias; Familial Combined Hyperlipidemia; Family; Genes; Genetic; Genetic Predisposition to Disease; Genome Scan; Healthcare Systems; Hepatic; High Density Lipoprotein Cholesterol; 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）：冠状动脉疾病（CHD）是美国和墨西哥死亡的主要原因。不利的血清脂质水平，例如高血清总胆固醇，高血清甘油三酸酯和低密度脂蛋白胆固醇，是CHD的众所周知的危险因素。尽管几项研究表明，墨西哥人口对血脂异常的倾向增加，但对于赋予这种敏感性的遗传因素，这种人群不足。考虑到墨西哥裔美国人在美国的迅速增长，对墨西哥人口的这些遗传因素的调查非常重要，并且与这一美国少数群体有关。为了确定在墨西哥人赋予高血清脂质水平的易感性的遗传变异，我们最近开始了在加州大学洛杉矶分校，洛杉矶，洛杉矶的调查人员与墨西哥城的Nacional de ciencias y Nutricion之间的国际合作。我们检查了24个扩展的墨西哥家族性高脂血症（FCHL）家族的一个基因和7个先前在高加索家族中用于FCHL的染色体基因座。 FCHL是易感冠心病的最常见的混合血脂异常，墨西哥人估计患病率为8％。我们证明了上游转录因子1（USF1）基因和10q和16q的染色体基因座与墨西哥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FCH​​L疾病的遗传成分的研究。最近，我们还确定了墨西哥人的肝核因子4，α（HNF4A）基因（HNF4A）基因（HNF4A）基因中的DMA变体之间的显着关联。尽管HNF4A变体以前已经与2型糖尿病（T2DM）相关联，但我们的数据首次显示HNF4A变体与血清脂质水平相关联。考虑到T2DM和FCHL之间明显的表型重叠，我们假设HNF4A是FCHL作为WEJI的良好候选基因。我们建议确定墨西哥人常见脂质疾病的新型敏感性基因座，并进一步研究这些涉及的基因。在特定目标1中，我们将在墨西哥FCHL家族中进行基因组扫描，以在先前研究的高加索人群中识别未发现或不存在的其他易感性基因座。在特定的目标2中，我们将研究USF1，HNF4A和染色体基因座与基因组扫描有关的染色体基因座，以表征DNA变体赋予墨西哥人对FCHL的易感性。