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

Jasper J Brugts*, Aaron Isaacs, Moniek Pm de Maat, Eric Boersma, Cock M van Duijn, K Martijn Akkerhuis, Andre G Uitterlinden, Jacqueline Cm Witteman, Francois Cambien, Claudio Ceconi, Willem Remme, Michel Bertrand, Toshiharu Ninomiya, Stephen Harrap, John Chalmers, Stephen Macmahon, Kim Fox, Roberto Ferrari, Maarten L Simoons, Ah Jan Danser

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


AIMS: 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.

METHODS AND 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.

CONCLUSION: This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals.

Original languageEnglish
Pages (from-to)509-19
Number of pages11
JournalJournal of Hypertension
Issue number3
Publication statusPublished - Mar 2011
Externally publishedYes


  • Aged
  • Angiotensin-Converting Enzyme Inhibitors/pharmacology
  • Angiotensinogen/genetics
  • Blood Pressure/drug effects
  • Female
  • Haplotypes
  • Humans
  • Hypertension/drug therapy
  • Male
  • Middle Aged
  • Peptidyl-Dipeptidase A/genetics
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide
  • Receptors, Cell Surface/genetics

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