Genetic determinants of total cholesterol levels in American Indians

美洲印第安人总胆固醇水平的遗传决定因素

• 批准号: 8231277
• 负责人: Johanna K DiStefano
• 金额: $ 56.34万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231277
• 关键词: 19p; 19p13.1; Accounting; Address; Affect; African American; Alleles; American Indians; Amino Acid Substitution; Applications Grants; Area; Bar Codes; Cause of Death; Cholesterol; Cholesterol Homeostasis; Chromosomes; Chromosomes, Human, Pair 19; Coronary heart disease; Custom; Data Linkages; Development; Disease; Ethnic group; Familial disease; Family; Fasting; Functional disorder; Gall Bladder Diseases; General Population; Genes; Genetic; Genetic Determinism; Genome; Genomics; Genotype; Goals; Haplotypes; Heart Diseases; Immunofluorescence Immunologic; In Vitro; Individual; Investigation; Knowledge; Lead; Link; Linkage Disequilibrium Mapping; Lipids; Lipoproteins; Low-Density Lipoproteins; Maps; Messenger RNA; Methods; Mexican Americans; Molecular; Monitor; Mutation; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Pattern; Pima Indian; Population; Process; Protein Binding; Proteins; Quantitative Trait Loci; RNA Splicing; Regulation; Resources; Risk; Risk Factors; Sampling; Sampling Studies; Serum; Single Nucleotide Polymorphism; Technology; Testing; United States; Validation; Variant; Western Blotting; base; density; design; genetic variant; heart disease risk; hypercholesterolemia; improved; innovation; interest; lipid metabolism; next generation; novel; protein expression; public health relevance; trait; transmission process; treatment strategy

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.

描述（由申请人提供）：导致心脏病发作和心绞痛的冠心病（CHD）是美国唯一的主要死亡原因。CHD发展的最强风险因素包括脂质和脂蛋白的循环水平，这两者都受到遗传因素的强烈调节。对血脂水平有显著影响的变异体已被确定为一些单基因家族性疾病，但这些仅占CHD的一小部分。相反，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识别和表征有助于调节空腹血清总胆固醇浓度的遗传变异。这项研究的重点是一个位点，它最初已被定位的基础上连锁数据的19号染色体在至少15项研究，然后缩小到1-LOD支持间隔<15.7 cM的皮马印第安人。该提案的具体目标是首先通过对2，884名皮马印第安人的研究样本中的一组密集SNP标记进行基因分型，对19 p上空腹血清TC浓度的QTL进行优化和优先定位。然后对来自NIDDM遗传学（GENNID）研究的701名非裔美国人（我们先前观察到其与TC浓度相关）和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共享更大的遗传相似性）的所有QTL相关SNP等位基因和单倍型进行基因分型。这一目标的完成将验证目标1中获得的结果。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性影响的特定变体。最后，我们提出了一个探索性的功能特性与强大的QTL相关的等位基因，这将提供一个基础的发展，一个全面的调查的分子机制，这些特定的变异影响调节胆固醇代谢的重点是一个独立的赠款申请。结合起来，这些目标将确定对空腹总胆固醇浓度具有关键影响的新变体。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的病理生理学的认识。 公共卫生相关性：总胆固醇水平受遗传因素控制。本研究的目的是通过鉴定和表征在许多不同人群中与19号染色体相关的基因，来提高我们对常见脂质异常（如高胆固醇血症）的认识。对调节胆固醇代谢的基因的鉴定和表征将增强我们对常见脂质异常遗传的理解，为发展心脏病的最大风险的目标个体提供标记物，并可能导致高胆固醇血症的治疗策略的改进。