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: 8060599
• 负责人: Johanna K DiStefano
• 金额: $ 42.25万
• 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/8060599
• 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状动脉疾病（CHD）是美国的单一主要死亡原因。冠心病发育的最强危险因素包括脂质和脂蛋白的循环水平，两者都受遗传因素的强烈调节。已经确定了许多单基因疾病对脂质水平有显着影响的变体，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遗传变异，这有助于调节总胆固醇的空腹血清浓度。这项研究的重点是一个基因座，该基因座最初是根据至少15个研究中的染色体数据与第19染色体的连锁数据进行了映射的，然后随后在皮马印第安人中缩小到1-LOD支撑间隔<15.7 cm。该提案的具体目标是首先优先改善QTL的定位，以在2,884名PIMA印第安人的研究样本中通过基因分型对19p的空腹血清TC浓度进行19P的禁食血清浓度。然后，所有与QTL相关的SNP等位基因和单倍型都将在NIDDM（GenNID）研究中的701个非洲裔美国人的个体中进行基因分型，我们以前已经观察到TC浓度的联系，而来自San Antonio Family gallbladder疾病研究的740个墨西哥裔美国人（SAFGS）具有更大的可能性（SAFGES），他们更有可能具有PEA的概念。该目标的完成将提供AIM 1中获得的发现的验证。下一步将利用创新的条形码方法来实现下一代测序，以完全表征显示与TC浓度相关的区域，并确定可能对胆固醇代谢的特定变体。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，这将为开发对分子机制的全面研究提供基础，通过该研究这些特定变体会影响胆固醇代谢的调节作为独立授予应用的重点。这些目标结合在一起，将确定对禁食总胆固醇浓度具有关键作用的新型变体。鉴定影响胆固醇浓度的遗传机制将提高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知识。 公共卫生相关性：总胆固醇水平受遗传因素的控制。这项研究的目的是通过鉴定和表征与许多不同种群中与19号染色体相关的基因的鉴定和表征来提高我们对常见脂质异常的了解，例如高胆固醇血症。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，为针对患有最大风险患心脏病风险的个体提供标记，并有可能改善高胆固醇血症的治疗策略。