ADMIXTURE MAPPING IDENTIFIES ASSOCIATION OF THE VNN1 GENE WITH HYPERTENSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 现代社会的移民模式创造了将人口混合作为识别易感基因的一种策略的机会。为了实施这一策略，我们在非洲裔美国人(N=1743)、欧洲裔美国人(N=1000)和墨西哥裔美国人(N=581)的随机人群样本中，对2270个单核苷酸多态的高信息量祖先标记组进行了基因分型。然后，我们检查了来自两个祖先群体之一的病例过度传播特定基因座的证据。高血压病例和对照组的定义基于标准的临床标准。在非裔美国人中进行了仅病例和病例对照分析。通过全基因组标记，我们复制了我们之前在6号和21号染色体上的混合作图研究中发现的结果。在病例对照分析中，我们对分布在18.3Mb区域的36个基因中的51个错义SNPs进行了基因分型。进一步的分析表明，VNN1基因中的错义SNP rs2272996(或N131S)与非裔美国人的高血压显著相关，这种关系在墨西哥裔美国人中也是如此；在欧洲裔美国人中观察到了不明显的相反关联。这个SNP也解释了在6号染色体的混合分析中观察到的大部分证据。尽管有这些令人鼓舞的结果，高血压的易感基因非常难以定位，需要独立研究的证实才能确立这些发现。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Migration patterns in modern societies have created the opportunity to use population admixture as a strategy to identify susceptibility genes. To implement this strategy, we genotyped a highly informative ancestry marker panel of 2270 single nucleotide polymorphisms in a random population sample of African Americans (N = 1743), European Americans (N = 1000) and Mexican Americans (N = 581). We then examined the evidence for over-transmission of specific loci to cases from one of the two ancestral populations. Hypertension cases and controls were defined based on standard clinical criteria. Both case-only and case-control analyses were performed among African Americans. With the genome-wide markers we replicated the findings identified in our previous admixture mapping study on chromosomes 6 and 21. For case-control analysis, we then genotyped 51 missense SNPs in 36 genes spaced across an 18.3 Mb region. Further analyses demonstrated that the missense SNP rs2272996 (or N131S) in the VNN1 gene was significantly associated with hypertension in African Americans and the association was replicated in Mexican Americans; a non-significant opposite association was observed in European Americans. This SNP also accounted for most of the evidence observed in the admixture analysis on chromosome 6. Despite these encouraging results, susceptibility loci for hypertension have been exceptionally difficult to localize and confirmation by independent studies will be necessary to establish these findings.