Adeyemo Adebowale, Gerry Norman, Chen Guanjie, Herbert Alan, Doumatey Ayo, Huang Hanxia, Zhou Jie, Lashley Kerrie, Chen Yuanxiu, Christman Michael, Rotimi Charles
Center for Research on Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
PLoS Genet. 2009 Jul;5(7):e1000564. doi: 10.1371/journal.pgen.1000564. Epub 2009 Jul 17.
The evidence for the existence of genetic susceptibility variants for the common form of hypertension ("essential hypertension") remains weak and inconsistent. We sought genetic variants underlying blood pressure (BP) by conducting a genome-wide association study (GWAS) among African Americans, a population group in the United States that is disproportionately affected by hypertension and associated complications, including stroke and kidney diseases. Using a dense panel of over 800,000 SNPs in a discovery sample of 1,017 African Americans from the Washington, D.C., metropolitan region, we identified multiple SNPs reaching genome-wide significance for systolic BP in or near the genes: PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger) and CACNA1H (a voltage-dependent calcium channel), are potential candidate genes for BP regulation and the latter is a drug target for a class of calcium channel blockers. No variant reached genome wide significance for association with diastolic BP (top scoring SNP rs1867226, p = 5.8 x 10(-7)) or with hypertension as a binary trait (top scoring SNP rs9791170, p = 5.1 x 10(-7)). We replicated some of the significant SNPs in a sample of West Africans. Pathway analysis revealed that genes harboring top-scoring variants cluster in pathways and networks of biologic relevance to hypertension and BP regulation. This is the first GWAS for hypertension and BP in an African American population. The findings suggests that, in addition to or in lieu of relying solely on replicated variants of moderate-to-large effect reaching genome-wide significance, pathway and network approaches may be useful in identifying and prioritizing candidate genes/loci for further experiments.
常见形式高血压（“原发性高血压”）的遗传易感性变异存在的证据仍然薄弱且不一致。我们通过在美国非裔人群中开展全基因组关联研究（GWAS）来寻找血压（BP）相关的遗传变异，美国非裔人群受高血压及其相关并发症（包括中风和肾脏疾病）的影响尤为严重。在来自华盛顿特区大都市区的1017名非裔美国人的发现样本中，使用超过80万个单核苷酸多态性（SNP）的密集芯片，我们在以下基因或其附近鉴定出多个达到全基因组显著性水平的收缩压相关SNP：PMS1、SLC24A4、YWHA7、IPO7和CACNA1H。其中两个基因，SLC24A4（一种钠/钾/钙交换器）和CACNA1H（一种电压依赖性钙通道），是血压调节的潜在候选基因，后者是一类钙通道阻滞剂的药物靶点。没有变异达到与舒张压关联的全基因组显著性水平（得分最高的SNP rs1867226，p = 5.8×10⁻⁷）或与作为二元性状的高血压关联的全基因组显著性水平（得分最高的SNP rs9791170，p = 5.1×10⁻⁷）。我们在西非人的样本中重复验证了一些显著的SNP。通路分析显示，携带得分最高变异的基因聚集在与高血压和血压调节具有生物学相关性的通路和网络中。这是首次在非裔美国人群中进行的高血压和血压全基因组关联研究。研究结果表明，除了仅依靠达到全基因组显著性水平的中等到大效应的重复变异之外，或者作为替代方法，通路和网络方法可能有助于识别和优先选择候选基因/位点以进行进一步实验。
