Caulfield Mark, Munroe Patricia, Pembroke Janine, Samani Nilesh, Dominiczak Anna, Brown Morris, Benjamin Nigel, Webster John, Ratcliffe Peter, O'Shea Suzanne, Papp Jeanette, Taylor Elizabeth, Dobson Richard, Knight Joanne, Newhouse Stephen, Hooper Joel, Lee Wai, Brain Nick, Clayton David, Lathrop G Mark, Farrall Martin, Connell John
Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine, London, UK.
Lancet. 2003 Jun 21;361(9375):2118-23. doi: 10.1016/S0140-6736(03)13722-1.
Blood pressure may contribute to 50% of the global cardiovascular disease epidemic. By understanding the genes predisposing to common disorders such as human essential hypertension we may gain insights into novel pathophysiological mechanisms and potential therapeutic targets. In the Medical Research Council BRItish Genetics of HyperTension (BRIGHT) study, we aim to identify these genetic factors by scanning the human genome for susceptibility genes for essential hypertension. We describe the results of a genome scan for hypertension in a large white European population.
We phenotyped 2010 affected sibling pairs drawn from 1599 severely hypertensive families, and completed a 10 centimorgan genome-wide scan. After rigorous quality control, we analysed the genotypic data by non-parametric linkage, which tests whether genes are shared in excess among the affected sibling pairs. Lod scores, calculated at regular points along each chromosome, were used to assess the support for linkage.
Linkage analysis identified a principle locus on chromosome 6q, with a lod score of 3.21 that attained genome-wide significance (p=0.042). The inclusion of three further loci with lod scores higher than 1.57 (2q, 5q, and 9q) also show genome-wide significance (p=0.017) when assessed under a locus-counting analysis.
These findings imply that human essential hypertension has an oligogenic element (a few genes may be involved in determination of the trait) possibly superimposed on more minor genetic effects, and that several genes may be tractable to a positional cloning strategy.
血压可能导致全球50%的心血管疾病流行。通过了解导致人类原发性高血压等常见疾病的易感基因，我们或许能深入了解新的病理生理机制和潜在的治疗靶点。在医学研究理事会英国高血压遗传学（BRIGHT）研究中，我们旨在通过扫描人类基因组寻找原发性高血压的易感基因来确定这些遗传因素。我们描述了在一个大型欧洲白人人群中进行的高血压基因组扫描结果。
我们对从1599个重度高血压家庭中选取的2010对患病同胞对进行了表型分析，并完成了10厘摩的全基因组扫描。经过严格的质量控制后，我们通过非参数连锁分析对基因分型数据进行分析，该分析测试患病同胞对中基因是否过度共享。沿每条染色体的固定点计算的对数优势分数用于评估连锁支持度。
连锁分析在6号染色体q臂上确定了一个主要位点，对数优势分数为3.21，达到全基因组显著性水平（p = 0.042）。在基因座计数分析中评估时，纳入另外三个对数优势分数高于1.57的位点（2号染色体q臂、5号染色体q臂和9号染色体q臂）也显示出全基因组显著性（p = 0.017）。
这些发现表明，人类原发性高血压具有寡基因成分（少数基因可能参与该性状的决定），可能叠加在较小的遗传效应之上，并且几个基因可能适用于定位克隆策略。
