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

基本信息

批准号：
8231853
负责人：
Johanna K DiStefano
金额：
$ 9.12万
依托单位：
TRANSLATIONAL GENOMICS RESEARCH INST
依托单位国家：
美国
项目类别：
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/8231853
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

项目摘要

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）：冠心病 (CHD) 会导致心脏病发作和心绞痛，是美国唯一的主要死亡原因。发生先心病的最强危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。已鉴定出对血脂水平有显着影响的变异体可用于许多单基因家族性疾病，但这些变异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。本研究的重点是一个基因座，该基因座最初是根据至少 15 项研究中 19 号染色体的连锁数据绘制的，然后在皮马印第安人中缩小到 1-LOD 支持区间 <15.7 cM。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一组密集的 SNP 标记进行基因分型，对 19p 空腹血清 TC 浓度的 QTL 定位进行细化和优先化。然后，将对来自 NIDDM (GENNID) 遗传学研究的 701 名非裔美国人个体（我们之前在这些人中观察到 TC 浓度的关联）和来自圣安东尼奥家族胆囊病的 740 名墨西哥裔美国人个体中的所有 QTL 相关 SNP 等位基因和单倍型进行基因分型研究（SAFGS）发现，他们更有可能与皮马印第安人有更大的遗传相似性。这一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，并识别可能发挥功能的特定变异。对胆固醇代谢的影响。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。独立的拨款申请。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异。确定影响胆固醇浓度的遗传机制将增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了解。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许多不同人群中与 19 号染色体相关的基因，增进我们对常见脂质异常（例如高胆固醇血症）的了解。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，为针对心脏病风险最大的个体提供标记，并有可能改善高胆固醇血症的治疗策略。