Cloning a Blood Pressure Gene on Human Chromosome 2q32.3

描述(由申请人提供)：旧秩序阿米什人是一个独特的封闭的创始人群体，他们的基因相对同质，拥有非常大的家庭规模和良好的家谱记录。通过全基因组连锁分析，我们在染色体2q31-q24上发现了一个与舒张压(LOD=4.23)和收缩压(LOD=1.61)都有强连锁的区域。通过我们正在进行的连锁不平衡(LD)定位和阿米什候选基因的定位分析，我们已经在2q32.2找到了一个约700kb的关键区域，该区域与BP密切相关。最近，通过更精细的LD与Framingham心脏研究(FHS)1,800多个DMA样本中的SNPs的映射，我们已经将BP相关区域定位到大约137kb的长度。本应用的目的是定位克隆染色体2q32.2上可能的血压基因。AIM 1将利用定位候选基因方法，在FHS和CARDIA队列的阿米什人、高加索人和非裔美国人中，对该地区所有EST和预测基因的序列变异进行鉴定、基因分型和关联分析。具体目标2将通过对3-5kb的SNP进行基因分型和关联分析，利用系统的LD作图。3个种群中临界区域的间隔时间。特定的目标3，即“终局游戏”，将设法确定目标1和2中确定的相关单倍型区块中的所有序列变异，然后进行DNA测序、基因分型和关联分析的迭代过程。最后，我们将测试最鼓舞人心的SNPs(和单倍型)是否可以解释阿米什人最初的连锁。影响血压的基因的发现将提供(I)对分子机制的关键见解；(Ii)治疗学的新分子靶点；以及(Iii)血液测试，以早期发现易感人群，以便制定有针对性的预防性干预措施。这些进步将对数百万美国人的生活质量产生重大影响。

DESCRIPTION (provided by applicant): The Old Order Amish are a unique closed founder population who are relatively genetically homogeneous, and have very large family sizes and well documented genealogies. Through genome wide linkage analysis, we identified a region of strong linkage to both diastolic (LOD = 4.23) and systolic (LOD = 1.61) blood pressure (BP) on chromosome 2q31-q24. Through our ongoing linkage disequilibrium (LD) mapping and positional candidate gene analyses in the Amish, we have identified a critical region of about 700 kb at 2q32.2 that is strongly associated with BP. Most recently, through finer LD mapping with SNPs in over 1,800 DMA samples from the Framingham Heart Study (FHS), we have localized the BP-associated region to approximately 137 kb in length. The objective of this application is to positionally clone the putative blood pressure gene on chromosome 2q32.2. Aim 1 will utilize a positional candidate gene approach in which sequence variation within all of the ESTs and predicted genes in the region will be identified, genotyped, and association analyses performed in the Amish, and outbred Caucasian and African Americans of the FHS and CARDIA cohorts. Specific Aim 2 will utilize systematic LD mapping through genotype and association analysis of SNPs spaced at 3 - 5 kb. intervals across the critical region in the 3 populations. Specific Aim 3, the "end game", will seek to identify all sequence variation in the associated haplotype block identified in Aims 1 and 2 followed by the iterative process of DNA sequencing, genotyping, and association analysis. Finally, we will test if the most encouraging SNPs (and haplotype) can account for the original linkage in the Amish. Discovery of genes influencing blood pressure will provide (i) critical insights into molecular mechanisms; (ii) new molecular targets for therapeutics; and (iii) blood tests for the early detection of susceptible individuals so that targeted preventative interventions can be instituted. These advances will impact substantially on the quality of life of millions of Americans.