Genetic susceptibility to Common Lipid Disorders in Mexico

描述(申请人提供)：在美国和墨西哥，冠心病(CHD)都是主要的死亡原因。不良的血脂水平，如高血清总胆固醇、高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。虽然几项研究表明墨西哥人对血脂异常的易感性增加，但这一人群对导致这种易感性的遗传因素调查不足。考虑到美国墨西哥裔美国人口的快速增长，调查墨西哥人口中的这些遗传因素对这一美国少数民族来说非常重要和相关。为了确定墨西哥人对高血脂水平的易感性的基因变异，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和营养研究所的研究人员之间的国际合作。我们检查了24个扩大的墨西哥家族性混合性高脂血症(FCHL)家系，检测了以前在高加索家庭中检测到的FCHL的一个基因和七个染色体位点。FCHL是最常见的易患CHD的混合性血脂异常，估计在墨西哥人中的患病率为8%。我们证实了上游转录因子1(USF1)基因和位于10q和16q上的染色体位点与墨西哥FCHL家族(Huertas-Vazquez等人)有关。2005)。这项研究是第一次广泛调查墨西哥人FCHL疾病的遗传成分。最近，我们还发现，在墨西哥人中，肝脏核因子4，α(HNF4a)基因的DMA变异与FCHL之间存在显著的关联。尽管HNF4a变异体以前与2型糖尿病(T2 DM)有关，但我们的数据首次显示HNF4a变异体与血脂水平有关。考虑到T2 DM和FCHL之间明显的表型重叠，我们推测HNF4a是FCHL作为weJI的一个很好的候选基因。我们建议在墨西哥人中确定新的常见血脂紊乱的易感基因，并进一步研究这些相关基因。在具体目标1中，我们将在墨西哥FCHL家族中进行基因组扫描，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基因。在特定的目标2中，我们将研究USF1、HNF4a和基因组扫描中涉及的染色体位点，以表征与墨西哥人FCHL易感性相关的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.