Genetic susceptibility to Common Lipid Disorders in Mexico

描述（由申请人提供）：冠心病（CHD）是美国和墨西哥的主要死亡原因。不利的血脂水平，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的危险因素。尽管几项研究表明，墨西哥人群对血脂异常的易感性增加，但该人群对赋予这种易感性的遗传因素的调查不足。考虑到墨西哥裔美国人在美国人口的快速增长，对墨西哥裔人口中这些遗传因素的研究非常重要，也与这一美国少数民族有关。为了确定墨西哥人对高血脂易感性的遗传变异，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营养研究所的研究人员之间的国际合作。我们对24个墨西哥家族合并高脂血症（FCHL）家族进行了1个基因和7个染色体位点的检测，这些基因和位点之前在高加索家族中检测到FCHL。FCHL是最常见的易致冠心病的混合性血脂异常，在墨西哥的患病率估计为8%。我们证明了上游转录因子1 （USF1）基因和10q和16q上的染色体位点与墨西哥FCHL家族有关（Huertas-Vazquez et al. 2005）。这项研究首次广泛研究了墨西哥人FCHL疾病的遗传成分。最近，我们还发现了墨西哥人肝核因子4 α (HNF4A)基因的DMA变异与FCHL之间的显著关联。尽管HNF4A变异先前与2型糖尿病（T2DM）相关，但我们的数据首次显示HNF4A变异与血脂水平相关。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。我们建议确定墨西哥人常见脂质疾病的新易感位点，并进一步检查这些相关基因。在Specific Aim 1中，我们将对墨西哥FCHL家族进行基因组扫描，以确定在先前研究的高加索人群中未发现或不存在的其他易感位点。在特异性目标2中，我们将研究基因组扫描中涉及的USF1、HNF4A和染色体位点，以表征墨西哥人对FCHL易感性的DNA变异。

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.