title: Chromosome 2p shows significant linkage to antihypertensive response in the British Genetics of Hypertension Study.
abstract: 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 beta-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.
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom. sp24g@clinmed.gla.ac.uk
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.forename: Richard
authors.initials: R
authors.lastname: Dobson
authors.forename: Morris
authors.initials: M
authors.lastname: Brown
authors.forename: Nilesh
authors.initials: N
authors.lastname: Samani
authors.forename: David
authors.initials: D
authors.lastname: Clayton
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: John
authors.initials: J
authors.lastname: Webster
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Mark
authors.initials: M
authors.lastname: Caulfield
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: John M
authors.initials: JM
authors.lastname: Connell
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002889:Chromosomes, Human, Pair 2; D004232:Diuretics / Q000627:therapeutic use; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D008126:Lod Score; D008297:Male; D008875:Middle Aged
chemical_list: D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004232:Diuretics