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(Hypertension. 2006;47:603.)
© 2006 American Heart Association, Inc.

Part 2 Original Articles

Chromosome 2p Shows Significant Linkage to Antihypertensive Response in the British Genetics of Hypertension Study

Sandosh Padmanabhan; Chris Wallace; Patricia B. Munroe; Richard Dobson; Morris Brown; Nilesh Samani; David Clayton; Martin Farrall; John Webster; Mark Lathrop; Mark Caulfield; Anna F. Dominiczak; John M. Connell

From the BHF Glasgow Cardiovascular Research Centre (S.P., A.F.D., J.M.C.), University of Glasgow, United Kingdom; Clinical Pharmacology and Barts and the London Genome Centre (C.W., P.B.M., R.D., M.C.), William Harvey Research Institute, Barts and the London School of Medicine, London, United Kingdom; Clinical Pharmacology and the Cambridge Institute of Medical Research (M.B., D.C.), University of Cambridge, United Kingdom; Department of Cardiology (N.S.), University of Leicester, United Kingdom; Department of Cardiovascular Medicine (M.F.), University of Oxford, Wellcome Trust Centre for Human Genetics, United Kingdom; Clinical Pharmacology Unit (J.W.), Aberdeen Royal Infirmary, United Kingdom; and Centre National de Genotypage (M.L.), Evry, France.

Correspondence to Sandosh Padmanabhan, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G128TA, United Kingdom. E-mail sp24g{at}clinmed.gla.ac.uk

There is a lack of consistently linked loci influencing blood pressure and hypertension status, and this may be because of genetic or phenotypic heterogeneity. We hypothesize that stratification of subjects by response to antihypertensive drug groups could be used to stringently define subsets that will have reduced genetic and etiologic heterogeneity, by partitioning contrasting mechanisms of hypertension and, thus, enhancing gene finding. We investigated the British Genetics of Hypertension Study population, which is composed of 2142 severely hypertensive white affected sibling pairs. Nonresponse to antihypertensive therapy was defined as an on-treatment blood pressure of >140/90 mm Hg or a difference between prediagnosis and on-treatment blood pressure of <20 mm Hg. Of the nonresponders, there were 89 sibling pairs (AB) who were both on antihypertensive therapy that inhibit the renin–angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, or ß-blockers), and 76 sibling pairs (CD) who were both on drugs that do not (calcium channel blockers or diuretics). Nonparametric linkage analysis carried out using markers from a 10-cM genome scan and additional "grid tightening" markers showed significant linkage in the AB group on chromosome 2p (logarithm of odds=4.84 at 90.68 Kosambi cM) and suggestive linkage for the CD group on chromosome 10q (logarithm of odds=2.83 at 125.96 Kosambi cM). The AB linkage locus attained genomewide significance after simulation using 10 000 replicates (P=0.005). This locus may contain a gene for the salt-sensitive form of hypertension and/or a pharmacogenetic locus affecting drug response. We have demonstrated for the first time identification of a significant locus by partitioning different pathways of hypertension using drug response.

Key Words: antihypertensive therapy • genetics • hypertension, genetic • hypertension, sodium-dependent • renin-angiotensin system • race

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