The Angiotensinogen Gene and Human Hypertension

描述（由申请人提供）：原发性高血压影响至少25%的美国成年人，是心力衰竭、中风和肾脏疾病的主要危险因素。许多但不是所有的研究表明，血管紧张素原基因（AGT）的变异影响高血压的风险，但迄今为止进行的关联研究已受到遗传异质性和高血压作为一种表型的固有复杂性的影响。为了克服这些困难，我们将在从世界各地的人群中取样的1,600多个个体中对包括AGT在内的14.4 kb区域进行测序或基因分型。这将使我们能够充分探索AGT基因等位基因异质性、单倍型变异和群体分层潜力的程度。这些个体中约有600例未进行临床表征，将代表广泛的全球人类变异。另外500名受试者是CEPH收集的40个犹他州家系的成员。这些独特的家庭已被大量的遗传特征，他们现在正在进行表型的变量，包括人体测量，血液化学，血压测量，血浆和尿血管紧张素原。我们将通过检测多SNP AGT单倍型、血管紧张素原水平和血压之间的关联来解决遗传异质性问题。此外，将评估连锁不平衡模式，以确定最适合定位复杂性状基因的SNP的密度和性质。我们将通过对Gordon威廉姆斯博士收集的400名高血压患者和100名血压正常者进行广泛的SNP分型来解决高血压表型异质性的问题。已测试了这些临床特征良好的受试者在高钠和低钠摄入量下对输注血管紧张素II的反应。这种直接探针提供了一种更接近AGT基因功能的高血压内表型，从而对AGT单倍型变异与高血压风险之间的关系进行了更现实和更有信息量的评估。在我们的全球样本中AGT序列变异的系统发育分析将有助于评估关联研究中的人群分层。此外，这个样本将使我们能够测试的假设，即祖先T235 AGT等位基因提供了一个选择性优势，在撒哈拉以南非洲的钠缺乏的环境。这项分析的结果可能有助于解释为什么非洲裔美国人的高血压发病率较高。总之，我们对1,600多名受试者AGT变异的广泛分析将阐明该基因在原发性高血压中的作用，并将检验关于AGT进化的特定假设。

DESCRIPTION (provided by applicant): Essential hypertension affects at least 25 percent of American adults, and it is a primary risk factor for heart failure, stroke, and kidney disease. Many, but not all, studies have shown that variants of the angiotensinogen gene (AGT) affect the risk of hypertension, but association studies conducted to date have been compromised by genetic heterogeneity and by the inherent complexity of hypertension as a phenotype. To overcome these difficulties, we will sequence or genotype a 14.4 kb region including AGT in more than 1,600 individuals sampled from populations throughout the world. This will permit us to explore fully the extent of allelic heterogeneity, haplotype variation, and potential for population stratification in the AGT gene. Approximately 600 of these individuals are clinically uncharacterized and will represent a broad range of worldwide human variation. Another 500 subjects are members of 40 Utah pedigrees that are part of the CEPH collection. These unique families have been heavily characterized genetically, and they are now being phenotyped for variables that include anthropometrics, blood chemistries, blood pressure measures, and plasma and urinary angiotensinogen. We will address the issue of genetic heterogeneity by testing associations between multi-SNP AGT haplotypes, angiotensinogen levels, and blood pressure. In addition, linkage disequilibrium patterns will be assessed to determine the density and nature of SNPs best suited for localizing a gene underlying a complex trait. We will address the issue of phenotypic heterogeneity in hypertension by performing extensive SNP typing on a set of 400 hypertensives and 100 normotensives collected by Dr. Gordon Williams. These clinically well-characterized subjects have been tested for their response to infused angiotensin-II under high and low sodium intake. This direct probe provides a hypertension endophenotype that is closer to the function of the AGT gene, yielding a more realistic and informative assessment of the relationship between AGT haplotype variation and hypertension risk. A phylogenetic analysis of AGT sequence variation in our worldwide sample will help to assess population stratification in association studies. In addition, this sample will allow us to test the hypothesis that the ancestral T235 AGT allele provided a selective advantage in the sodium-poor environment of sub-Saharan Africa. The results of this analysis may help to explain why African-Americans have elevated rates of hypertension. In summary, our extensive analysis of AGT variation in more than 1,600 subjects will clarify the role of this gene in essential hypertension and will test specific hypotheses about the evolution of AGT.