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 P.M. De Maat, Eric Boersma, Cock M. Van Duijn, K. Martijn Akkerhuis, Andre G. Uitterlinden, Jacqueline C.M. Witteman, Francois Cambien, Claudio Ceconi, Willem Remme, Michel Bertrand, Toshiharu Ninomiya, Stephen Harrap, John Chalmers, Stephen MacMahon, Kim Fox, Roberto Ferrari, Maarten L. Simoons, A. H.Jan Danser

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Abstract

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)509-519
Number of pages11
JournalJournal of Hypertension
Volume29
Issue number3
DOIs
Publication statusPublished - Mar 2011
Externally publishedYes

Keywords

  • ACE inhibitors
  • gene
  • hypertension
  • PERGENE
  • pharmacogenetics
  • polymorphism
  • PROGRESS
  • renin-angiotensin-aldosterone system

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    Brugts, J. J., Isaacs, A., De Maat, M. P. M., Boersma, E., Van Duijn, C. M., Akkerhuis, K. M., Uitterlinden, A. G., Witteman, J. C. M., Cambien, F., Ceconi, C., Remme, W., Bertrand, M., Ninomiya, T., Harrap, S., Chalmers, J., MacMahon, S., Fox, K., Ferrari, R., Simoons, M. L., & Danser, A. H. J. (2011). 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. Journal of Hypertension, 29(3), 509-519. https://doi.org/10.1097/HJH.0b013e328341d117