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

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.

• Authors: 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
• Journal: Journal of hypertension (J Hypertens) Vol. 29 Issue 3 Pg. 509-19 (Mar 2011) ISSN: 1473-5598 [Electronic] England
• PMID: 21157371 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Receptors, Cell Surface
• Angiotensinogen
• Peptidyl-Dipeptidase A
• Prorenin Receptor

Topics

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