title: A pharmacogenetic analysis of determinants of hypertension and blood pressure response to angiotensin-converting enzyme inhibitor therapy in patients with vascular disease and healthy individuals.
abstract: OBJECTIVE
  To investigate whether genetic variation in the renin-angiotensin-aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients.
  
  
  RESULTS
  In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP ≥160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing.
  
  
  RESULTS
  Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4 mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro)renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2-3-fold increase (P for trend <0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis.
  
  
  CONCLUSIONS
  This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals.
authors.affiliation: Department of Cardiology, Erasmus MC Thoraxcenter, Rotterdam, The Netherlands. j.brugts@erasmusmc.nl
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: Brugts
authors.forename: Aaron
authors.initials: A
authors.lastname: Isaacs
authors.forename: Moniek Pm
authors.initials: MP
authors.lastname: de Maat
authors.forename: Eric
authors.initials: E
authors.lastname: Boersma
authors.forename: Cock M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: K Martijn
authors.initials: KM
authors.lastname: Akkerhuis
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Jacqueline Cm
authors.initials: JC
authors.lastname: Witteman
authors.forename: Francois
authors.initials: F
authors.lastname: Cambien
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceconi
authors.forename: Willem
authors.initials: W
authors.lastname: Remme
authors.forename: Michel
authors.initials: M
authors.lastname: Bertrand
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ninomiya
authors.forename: Stephen
authors.initials: S
authors.lastname: Harrap
authors.forename: John
authors.initials: J
authors.lastname: Chalmers
authors.forename: Stephen
authors.initials: S
authors.lastname: Macmahon
authors.forename: Kim
authors.initials: K
authors.lastname: Fox
authors.forename: Roberto
authors.initials: R
authors.lastname: Ferrari
authors.forename: Maarten L
authors.initials: ML
authors.lastname: Simoons
authors.forename: Ah Jan
authors.initials: AJ
authors.lastname: Danser
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000808:Angiotensinogen / Q000235:genetics*; D001794:Blood Pressure / Q000187:drug effects*; D005260:Female; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D000093342:Prorenin Receptor
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011956:Receptors, Cell Surface; D000808:Angiotensinogen; D007703:Peptidyl-Dipeptidase A; D000093342:Prorenin Receptor