Genome-wide mapping of human loci for essential hypertension

被引:203
作者
Caulfield, M
Munroe, P
Pembroke, J
Samani, N
Dominiczak, A
Brown, M
Benjamin, N
Webster, J
Ratcliffe, P
O'Shea, S
Papp, J
Taylor, E
Dobson, R
Knight, J
Newhouse, S
Hooper, J
Lee, W
Brain, N
Clayton, D
Lathrop, GM
Farrall, M
Connell, J
机构
[1] Queen Marys Sch Med, Barts & London, William Harvey Res Inst, Barts & London Genome Ctr, London EC1M 6BQ, England
[2] Univ Leicester, Glenfield Hosp, Leicester, Leics, England
[3] Univ Glasgow, Western Infirm, Div Cardiovasc & Med Sci, Glasgow G11 6NT, Lanark, Scotland
[4] Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res, Cambridge CB2 2QQ, England
[5] Aberdeen Royal Infirm, Aberdeen, Scotland
[6] Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Clin Med, Oxford, England
[7] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford, England
[8] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA
[9] Ctr Natl Genotypage, Evry, France
关键词
D O I
10.1016/S0140-6736(03)13722-1
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background 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. Methods 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, Findings 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. Interpretation 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.
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页码:2118 / 2123
页数:6
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