Blood Pressure Loci Identified with a Gene-Centric Array
Blood Pressure Loci Identified with a Gene-Centric Array
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DOI：
10.1016/j.ajhg.2011.10.013
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发表时间：
2011-12-09
影响因子：
9.8
通讯作者：
Munroe, Patricia B.
中科院分区：
文献类型：
--
作者：
Johnson, Toby;Gaunt, Tom R.;Munroe, Patricia B.
血压升高（BP）是心血管疾病的主要危险因素。以前的研究已经确定了47种与BP密切相关的不同遗传变异，但这些遗传变异只能解释BP表型遗传率的百分之几。为了找到更多的BP基因座，我们使用了一个定制的基因中心阵列对一个独立的发现样本进行基因分型，该样本包括25，118名个体，该样本将高血压病例对照和普通人群样本相结合。我们在我们的研究特异性显著性阈值p < 8.56 x 10（-7）下随访了4个与BP相关的SNP，并在另外59，349名个体中随访了6个与BP相关的SNP。我们鉴定并复制了LSP 1/TNNT 3的SNP，MTHFR-NPPB的SNP独立于先前的报道（r（2）= 0.33），并复制了先前报道的AGT和ATP 2B 1的SNP。结合发现和随访数据的分析确定了与BP显著相关的SNP，p < 8.56 x 10（-7），在另外四个位点（NPR 3，FIFE，NOS 3和SOX 6）。大量的发现与适度的基因分型的努力可以归因于使用大规模的，但有针对性的基因分型阵列和加权方案的发展，最大限度地提高功率时，荟萃分析结果与极端表型确定的样本，结合结果从未确定或人口样本。染色质免疫沉淀和转录表达数据突出了MTHFR和NOS 3位点的潜在基因调控机制。这些结果为进一步研究提供了候选人，以帮助剖析影响BP的机制，并强调研究SNP和样本的实用性，即使样本量小于以前的研究。
Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 x 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery, and follow-up data identified SNPs significantly associated with BP at p < 8.56 x 10(-7) at four further loci (NPR3, FIFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.