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，它是心力衰竭、中风和肾脏疾病的主要危险因素。许多（但不是全部）研究表明，血管紧张素原基因（AGT）的变异会影响高血压的风险，但迄今为止进行的相关研究受到遗传异质性和高血压作为表型的固有复杂性的影响。为了克服这些困难，我们将从世界各地的人群中取样1,600多个个体，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基因的等位基因异质性、单倍型变异和群体分层的潜力。这些个体中约有600人在临床上没有特征，并将代表世界范围内广泛的人类变异。另外500个对象是40个犹他血统的成员，是CEPH收藏的一部分。这些独特的家族在遗传上已经有了很大的特征，现在正在对包括人体测量学、血液化学、血压测量、血浆和尿血管紧张素原在内的变量进行表型分析。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的问题。此外，将评估连锁不平衡模式，以确定最适合定位复杂性状的基因的snp的密度和性质。我们将通过对Gordon Williams博士收集的400名高血压患者和100名正常血压患者进行广泛的SNP分型来解决高血压表型异质性的问题。这些临床特征良好的受试者在高钠和低钠摄入下对血管紧张素- ii输注的反应进行了测试。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，对AGT单倍型变异与高血压风险之间的关系提供了更现实、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群体分层。此外，该样本将使我们能够验证祖先的T235 AGT等位基因在撒哈拉以南非洲缺钠环境中提供选择优势的假设。这一分析结果可能有助于解释为什么非裔美国人高血压发病率较高。总之，我们对1600多名受试者的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，并将测试关于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.