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，家庭规模非常大，家谱记录良好。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）有强连锁关系的区域。通过我们正在进行的阿米什人的连锁不平衡（LD）定位和候选基因分析，我们在2q32.2上发现了一个约700 kb的关键区域，与BP密切相关。最近，通过对来自弗雷明汉心脏研究（FHS）的1800多个DMA样本的snp进行更精细的LD定位，我们将bp相关区域定位为大约137 kb的长度。本应用程序的目的是定位克隆染色体2q32.2上假定的血压基因。Aim 1将利用定位候选基因方法，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，并对FHS和CARDIA队列中的阿米什人、近亲繁殖的高加索人和非裔美国人进行关联分析。特异性目标2将利用系统的LD定位，通过基因型和关联分析间隔在3 - 5kb的snp。3个种群中临界区域的间隔。具体目标3是“最终游戏”，将通过DNA测序、基因分型和关联分析的迭代过程，寻求识别目标1和目标2中确定的相关单倍型块的所有序列变异。最后，我们将测试最令人鼓舞的单核苷酸多态性（和单倍型）是否能解释阿米什人的原始连锁。发现影响血压的基因将提供(1)对分子机制的关键见解；（ii）新的治疗分子靶点；（三）为早期发现易感个体进行血液检查，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.