Comprehensive Mapping of a Blood Pressure QTL on Chromosome 17

17 号染色体上血压 QTL 的综合定位

• 批准号: 7464874
• 负责人: Kari E. North
• 金额: $ 69.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-23 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464874
• 关键词: 17q; 17q24.2; 17q25.3; Accounting; Achievement; African American; Alleles; American; American Indians; Animals; Arts; Atherosclerosis; Base Pairing; Bioinformatics; Biological Assay; Blood Pressure; Candidate Disease Gene; Chromosomes; Chromosomes, Human, Pair 17; Clinical; Complex; DNA Library; DNA Resequencing; Data Set; Development; Disease; European; Evaluation; Facility Construction Funding Category; Family; Family Study; Family member; Future; Gene Frequency; Genes; Genetic; Genetic Databases; Genetic Polymorphism; Genetic Variation; Genome Scan; Genotype; Goals; Haplotypes; Heart; Hispanic Americans; Hypertension; Individual; Link; Linkage Disequilibrium Mapping; Literature; Localized; Lod Score; Maps; Measures; Minor; Molecular; Morbidity - disease rate; Natural History; Nucleotides; Numbers; Participant; Pathogenesis; Phenotype; Population; Population Programs; Predisposition; Public Health; Pulse Pressure; Quantitative Trait Loci; Resources; Risk; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Testing; Variant; Woman; Work; base; blood pressure regulation; cardiovascular disorder risk; cohort; experience; follow-up; genetic analysis; genetic epidemiology; genetic linkage analysis; genetic variant; genome-wide linkage; human study; novel; pressure; programs; sex; trait

DESCRIPTION (provided by applicant): This application aims to identify gene variants in chromosome 17 associated with blood pressure variation and susceptibility to hypertension, by following-up persuasive linkage findings of blood pressure in American Indian participants of the Strong Heart Family Study (SHFS). Prior genome-wide linkage analysis of 1894 SHFS participants detected evidence of a quantitative trait loci (QTL) influencing systolic blood pressure on chromosome 17q25.3. This region has been also identified in the Family Blood Pressure Program (FBPP) Hypertension Genetic Epidemiology Network (HyperGEN) and FBPP Genetics Epidemiology Network of Atherosclerosis (GENOA) participants for blood pressure-related traits and, therefore, may harbor genes with broad significance for blood pressure regulation. We propose to extend this work by comprehensively evaluating genetic variation in this chromosome 17q region in the large and informative cohort of the SHFS using state-of-the-art molecular and statistical genetic analyses. We will test the hypothesis that the chromosome 17 QTL contains one or more polymorphic variants that account for the linkage signal by performing comprehensive linkage disequilibrium mapping of the region in the SHFS samples. For genes with preliminary evidence of association, we will select the most promising candidate genes for resequencing and single nucleotide polymorphism (SNP) discovery. We will use the measured genotype approach and family based association to test for association of identified SNPs and/or haplotypes with our linked traits, while accounting for linkage. We plan to replicate our findings in the FBPP HyperGEN (N=3,855) and GENOA (N=5,174) samples of European American, African American and Hispanic American subjects. The prior findings of linkage of blood pressure traits to 17q in the FBPP population samples to be used for replication are exciting and may allow us to successfully identify gene variants influencing blood pressure and hypertension susceptibility. Identification of the risk alleles underlying this linkage peak may suggest novel mechanisms underlying blood pressure regulation and the development of hypertension. PUBLIC HEALTH RELEVANCE: Given the extensive morbidity associated with hypertension in the US and around the world, understanding its genetic basis is a critical step toward disease mitigation and treatment. The importance of studying hypertension in an American Indian population is highlighted by this population's elevated risk of cardiovascular disease, in addition to the gap in the literature for this relatively understudied group. The proposed study may expand our understanding of the impact of the genes on the natural history of hypertension and mechanisms of blood pressure control.

描述（由申请人提供）：本申请旨在通过跟踪美国印第安人强心脏家庭研究（SHFS）参与者血压的有说服力的联系发现，确定与血压变化和高血压易感性相关的17号染色体基因变异。先前对1894名SHFS参与者的全基因组连锁分析发现，染色体17q25.3上存在影响收缩压的数量性状位点（QTL）。该区域在家庭血压计划（FBPP）高血压遗传流行病学网络（HyperGEN）和FBPP动脉粥样硬化遗传流行病学网络（GENOA）参与者中也发现了与血压相关的特征，因此可能包含对血压调节具有广泛意义的基因。我们建议通过使用最先进的分子和统计遗传分析，在SHFS的大型信息性队列中全面评估该染色体17q区域的遗传变异，从而扩展这项工作。我们将通过在SHFS样本中对该区域进行全面的连锁不平衡定位，来验证17号染色体QTL包含一个或多个解释连锁信号的多态性变异的假设。对于有初步关联证据的基因，我们将选择最有希望的候选基因进行重测序和单核苷酸多态性（SNP）发现。我们将使用测量的基因型方法和基于家族的关联来测试鉴定的snp和/或单倍型与我们相关性状的关联，同时考虑连锁。我们计划在FBPP HyperGEN （N=3,855）和GENOA （N=5,174）样本中复制我们的发现，这些样本包括欧洲裔美国人、非洲裔美国人和西班牙裔美国人。在FBPP人群样本中，用于复制的血压性状与17q的联系的先前发现令人兴奋，并可能使我们成功识别影响血压和高血压易感性的基因变异。确定这一连锁峰值的风险等位基因可能提示血压调节和高血压发展的新机制。公共卫生相关性：鉴于高血压在美国和世界范围内的广泛发病率，了解其遗传基础是缓解和治疗疾病的关键一步。美洲印第安人患心血管疾病的风险较高，以及这一研究相对不足的群体的文献空白，凸显了研究美洲印第安人高血压的重要性。这项研究可能会扩大我们对基因对高血压自然历史和血压控制机制的影响的理解。