title: Pharmacogenomics of hypertension: a genome‐wide, placebo‐controlled cross‐over study, using four classes of antihypertensive drugs.
abstract: BACKGROUND
  Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment.
  
  
  RESULTS
  We conducted a genome-wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double-blind, placebo-controlled cross-over study where each subject received amlodipine, bisoprolol,hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry (PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single-nucleotide polymorphisms within the ACY3 gene that showed associations with bisoprolol response reaching genome-wide significance (P<5x10(-8))however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single-nucleotide polymorphisms showed P values of 10(-5) to 10(-7). The 20 top-associated single-nucleotide polymorphisms were different for each antihypertensive drug. None of these top single-nucleotide polymorphisms co-localized with the panel of >40 genes identified in genome-wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH1A3 (rs3825926) and CLIC5 (rs321329) genes.
  
  
  CONCLUSIONS
  These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenase–mediated reactions in antihypertensive drug action.
authors.forename: Timo P
authors.initials: TP
authors.lastname: Hiltunen
authors.forename: Kati M
authors.initials: KM
authors.lastname: Donner
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Sarin
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: John G
authors.initials: JG
authors.lastname: Gums
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.forename: Francesca
authors.initials: F
authors.lastname: Frau
authors.forename: Valeria
authors.initials: V
authors.lastname: Glorioso
authors.forename: Roberta
authors.initials: R
authors.lastname: Zaninello
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.forename: Nicola
authors.initials: N
authors.lastname: Glorioso
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Kimmo K
authors.initials: KK
authors.lastname: Kontula
mesh_terms: D000328:Adult; D000445:Aldehyde Oxidoreductases / Q000235:genetics; D017311:Amlodipine / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D017298:Bisoprolol / Q000627:therapeutic use; D018660:Blood Pressure Monitoring, Ambulatory; D018118:Chloride Channels / Q000235:genetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000075222:Essential Hypertension; D005387:Finland; D055106:Genome-Wide Association Study; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D015201:Meta-Analysis as Topic; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D013777:Tetrazoles / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C411466:CLIC5 protein, human; D018118:Chloride Channels; D008565:Membrane Proteins; D008840:Microfilament Proteins; D013777:Tetrazoles; C113267:nephrin; D006852:Hydrochlorothiazide; D017311:Amlodipine; D000445:Aldehyde Oxidoreductases; C018699:aldehyde dehydrogenase (NAD(P)+); D019808:Losartan; C081643:candesartan; D017298:Bisoprolol