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。虽然几项研究表明，墨西哥人口有增加的易感性血脂异常，这一人口是调查不足的遗传因素赋予这种易感性。考虑到美国墨西哥裔美国人人口的快速增长，在墨西哥人群中调查这些遗传因素是非常重要的，也与这个美国少数民族有关。为了确定墨西哥人对高血脂水平易感的遗传变异，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科学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个墨西哥家族性混合性高脂血症（FCHL）大家族，以寻找之前在高加索家族中检测到的FCHL基因和7个染色体位点。FCHL是最常见的混合性血脂异常，易患冠心病，估计在墨西哥人中的患病率为8%。我们证明了上游转录因子1（USF 1）基因和10 q和16 q上的染色体位点与墨西哥FCHL家族有关（Huertas-Vazquez et al. 2005）。这项研究是第一个广泛调查墨西哥人FCHL疾病遗传成分的研究。最近，我们还确定了墨西哥人肝核因子4 α（HNF 4A）基因的DMA变体与FCHL之间的显著关联。尽管HNF 4A变异体以前与2型糖尿病（T2 DM）相关，但我们的数据首次显示HNF 4A变异体与血脂水平相关。考虑到T2 DM和FCHL之间明显的表型重叠，我们假设HNF 4A是FCHL的良好候选基因，如weJI。我们建议确定新的易感基因位点，常见的脂质紊乱的墨西哥人，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，以确定先前研究的高加索人群中未发现或不存在的其他易感性位点。在具体目标2中，我们将研究USF 1，HNF 4A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。

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.