Comprehensive Mapping of a Blood Pressure QTL on Chromosome 17

描述(申请人提供)：这项申请旨在通过跟踪强大心脏家族研究(SHFS)的美国印第安人参与者血压的有说服力的连锁发现，识别与血压变异和高血压易感性相关的17号染色体上的基因变异。之前对1894名SHFS参与者进行的全基因组连锁分析发现，有证据表明染色体17q25.3上有一个影响收缩压的数量性状基因座(QTL)。该区域也已在家庭血压计划(FBPP)高血压遗传流行病学网络(HyperGEN)和热那亚动脉粥样硬化(Genoa)参与者的FBPP遗传流行病学网络中发现了与血压相关的性状，因此可能包含对血压调节具有广泛意义的基因。我们建议扩展这项工作，通过使用最先进的分子和统计遗传分析，在SHFS的大而有信息的队列中全面评估该染色体17q区域的遗传变异。我们将通过对SHFS样本中的该区域进行全面的连锁不平衡作图来检验这一假设，即17号染色体QTL包含一个或多个解释连锁信号的多态变异。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新测序和单核苷酸多态(SNP)发现。我们将使用测量的基因型方法和基于家庭的关联来测试已识别的SNPs和/或单倍型与我们的连锁性状的关联，同时考虑连锁。我们计划在欧洲裔美国人、非裔美国人和西班牙裔美国人的FBPP HyperGEN(N=3,855)和热那亚(N=5,174)样本中复制我们的发现。在用于复制的FBPP人群样本中，血压性状与17q连锁的先前发现令人兴奋，并可能使我们成功地识别影响血压和高血压易感性的基因变异。识别这种连锁高峰背后的风险等位基因可能会提示血压调节和高血压发展的新机制。公共卫生相关性：鉴于美国和世界各地与高血压相关的广泛发病率，了解其遗传基础是缓解和治疗疾病的关键一步。在美国印第安人人群中研究高血压的重要性因这一人群心血管疾病风险的增加而突显出来，此外，针对这一相对研究较少的人群的文献存在差距。这项拟议的研究可能会扩大我们对这些基因对高血压自然病史和血压控制机制的影响的理解。

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.