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人口谁是相对遗传同质，并有非常大的家庭规模和有据可查的家谱。通过全基因组连锁分析，我们在染色体2 q31-q24上确定了与舒张压（LOD = 4.23）和收缩压（LOD = 1.61）密切相关的区域。通过我们正在进行的连锁不平衡（LD）映射和位置候选基因分析在阿米什人，我们已经确定了一个关键区域约700 kb的2q32.2是强烈相关的BP。最近，通过对来自Frachial Heart Study（FHS）的1，800多个DMA样本中的SNP进行更精细的LD作图，我们已经将BP相关区域定位到约137 kb的长度。本申请的目的是定位克隆染色体2q32.2上的假定血压基因。目标1将利用位置候选基因的方法，在该方法中，将对该区域所有EST和预测基因内的序列变异进行鉴定、基因分型，并在FHS和CARDIA队列的阿米什人、远交高加索人和非洲裔美国人中进行关联分析。具体目标2将通过间隔为3 - 5 kb的SNP的基因型和关联分析利用系统LD作图。在3个种群中，临界区间。具体目标3，即“最终游戏”，将寻求鉴定目标1和2中鉴定的相关单倍型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，我们将测试最令人鼓舞的SNP（和单倍型）是否可以解释阿米什人的原始连锁。发现影响血压的基因将提供（i）对分子机制的重要见解;（ii）治疗的新分子靶点;（iii）用于早期检测易感个体的血液检测，以便制定有针对性的预防干预措施。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.