Genetic determinants of total cholesterol levels in American Indians

描述(申请人提供)：在美国，导致心脏病发作和心绞痛的冠心病(CHD)是导致死亡的唯一主要原因。CHD发展的最大风险因素包括循环中的脂类和脂蛋白水平，这两个因素都受到遗传因素的强烈调控。对血脂水平有显著影响的变异已经在一些单基因家族性疾病中被发现，但这些变异只占CHD的一小部分。相比之下，常见血脂异常的遗传决定因素仍不清楚。该项目的总体计划是识别和表征有助于调节空腹血清总胆固醇浓度的基因变异。这项研究的重点是一个在至少15项研究中根据连锁数据初步定位到19号染色体的基因座，随后缩小到PIMA印第安人的1-LOD支持区间&15.7 cM。这项建议的具体目标是首先通过在2884名皮马印度人的研究样本中对一组密集的SNP标记进行基因分型，首先精炼和优先定位用于19p上空腹血清TC浓度的QTL(S)。所有与QTL相关的SNP等位基因和单倍型将在来自NIDDM遗传学(GENNID)研究的701名非洲裔美国人和来自圣安东尼奥家族胆囊病研究(SAFGS)的740名墨西哥裔美国人中进行基因分型，这些人更有可能与PIMA印第安人有更大的遗传相似性。这一目标的完成将验证目标1中的发现。下一步将利用创新的条形码方法进行下一代测序，以充分表征与总胆固醇浓度相关的区域，并识别可能对胆固醇代谢产生功能影响的特定变异。最后，我们提出了与强QTL相关等位基因相关的功能效应的探索性表征，这将为全面研究这些特定变异影响胆固醇代谢调节的分子机制提供基础，作为独立赠款申请的重点。这些目标结合在一起，将识别对空腹总胆固醇浓度有关键影响的新变种。识别影响胆固醇浓度的遗传机制将促进我们对脂代谢的了解，从而增强对动脉粥样硬化过程的病理生理学的了解。

DESCRIPTION (provided by applicant): Coronary heart disease (CHD), which causes heart attacks and angina, is the single leading cause of death in the United States. The strongest risk factors for CHD development include circulating levels of lipids and lipoproteins, both of which are strongly regulated by genetic factors. Variants with significant effects on lipid levels have been identified for a number of monogenic familial disorders, but these account for only a small proportion of CHD. In contrast, genetic determinants for common lipid abnormalities remain unknown. The overall plan for this project is to identify and characterize genetic variants that contribute to the regulation of fasting serum concentrations of total cholesterol. The focus of this study is a locus which has been initially mapped on the basis of linkage data to chromosome 19 in at least 15 studies, then subsequently narrowed to a 1-LOD support interval <15.7 cM in Pima Indians. The specific goals of this proposal are to first refine and prioritize localization of the QTL(s) for fasting serum TC concentration on 19p by genotyping a dense set of SNP markers in a study sample of 2,884 Pima Indians. All QTL-associated SNP alleles and haplotypes will then be genotyped in 701 African American individuals from the Genetics of NIDDM (GENNID) study, in whom we have previously observed linkage for TC concentration, and 740 Mexican American individuals from the San Antonio Family Gallbladder Disease Study (SAFGS), who are more likely to share greater genetic similarity with Pima Indians. Completion of this aim will provide validation of findings obtained in Aim 1. The next step will utilize an innovative bar-code approach to next-generation sequencing to fully characterize regions showing association with TC concentration, and identify specific variants that are likely to exert functional effects on cholesterol metabolism. Finally, we propose an exploratory characterization of functional effects associated with strong QTL-related alleles, which will provide a basis for the development of a full-scale investigation of the molecular mechanisms by which these specific variants affect regulation of cholesterol metabolism as the focus of an independent grant application. Combined, these aims will identify novel variants with critical effects on fasting total cholesterol concentration. Identification of the genetic mechanisms influencing cholesterol concentrations will advance our understanding of lipid metabolism, leading to an enhanced knowledge of the pathophysiology of the atherosclerotic process.