Genetic determinants of total cholesterol levels in American Indians

描述（由申请人提供）：冠心病（CHD），导致心脏病发作和心绞痛，是美国唯一的主要死亡原因。冠心病发生的最大危险因素包括血脂和脂蛋白的循环水平，这两者都受遗传因素的强烈调节。对脂质水平有显著影响的变异已被确定为许多单基因家族性疾病，但这些只占冠心病的一小部分。相比之下，常见脂质异常的遗传决定因素仍然未知。该项目的总体计划是确定和表征有助于调节空腹血清总胆固醇浓度的遗传变异。本研究的重点是一个基因座，该基因座在至少15项研究中最初基于19号染色体的连锁数据进行了定位，随后在皮马印第安人中缩小到1-LOD支持间隔<15.7 cM。本提案的具体目标是首先通过对2884名皮马印第安人的研究样本中密集的一组SNP标记进行基因分型，来完善和优先定位空腹血清TC浓度在19p上的QTL。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名非洲裔美国人以及来自圣安东尼奥家族胆囊疾病研究（SAFGS）的740名墨西哥裔美国人（他们更有可能与皮马印第安人具有更大的遗传相似性）中进行基因分型，我们之前在这些人中观察到TC浓度的连锁关系。该目标的完成将为目标1中获得的结果提供验证。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TC浓度相关的区域，并确定可能对胆固醇代谢产生功能影响的特定变体。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，这将为这些特定变异影响胆固醇代谢调节的分子机制的全面研究提供基础，作为独立资助申请的重点。综上所述，这些目标将确定对空腹总胆固醇浓度有关键影响的新变异。确定影响胆固醇浓度的遗传机制将促进我们对脂质代谢的理解，从而增强对动脉粥样硬化过程病理生理学的认识。

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. PUBLIC HEALTH RELEVANCE: Total cholesterol levels are under the control of genetic factors. The goal of this study is to advance our knowledge of common lipid abnormalities, such as hypercholesterolemia, through the identification and characterization of genes that have been linked to chromosome 19 in a number of different populations. Identification and characterization of genes that regulate cholesterol metabolism will enhance our understanding of the inheritance of common lipid abnormalities, provide markers to target individuals at greatest risk for developing heart disease, and potentially lead to improved treatment strategies for hypercholesterolemia.