Abstract | AIMS: METHODS AND RESULTS: In 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5% of the patients [hazard ratio (HR) 0.67; 95% confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5% (HR 1.26; 95% CI 0.97-1.67) with a trend towards a harmful effect. In 1051 patients with cerebrovascular disease from the PROGRESS-trial, treated with perindopril or placebo, an interaction effect of similar direction and magnitude, although not statistically significant, was observed. CONCLUSION: The current study is the first to identify genetic determinants of treatment benefit of ACE-inhibitor therapy. We developed a genetic profile which predicts the treatment benefit of ACE-inhibitors and which could be used to optimize therapy.
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Authors | Jasper Jan Brugts, Aaron Isaacs, Eric Boersma, Cock M van Duijn, Andre G Uitterlinden, Willem Remme, Michel Bertrand, Toshiharu Ninomiya, Claudio Ceconi, John Chalmers, Stephen MacMahon, Kim Fox, Roberto Ferrari, Jacqueline C M Witteman, A H Jan Danser, Maarten L Simoons, Moniek P M de Maat |
Journal | European heart journal
(Eur Heart J)
Vol. 31
Issue 15
Pg. 1854-64
(Aug 2010)
ISSN: 1522-9645 [Electronic] England |
PMID | 20538738
(Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
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Chemical References |
- Angiotensin-Converting Enzyme Inhibitors
- Receptor, Angiotensin, Type 1
- Receptor, Bradykinin B1
- Perindopril
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Topics |
- Angiotensin-Converting Enzyme Inhibitors
(therapeutic use)
- Coronary Artery Disease
(drug therapy, genetics)
- Female
- Gene Frequency
- Genotype
- Heart Arrest
(prevention & control)
- Humans
- Kallikrein-Kinin System
(genetics)
- Male
- Middle Aged
- Myocardial Infarction
(prevention & control)
- Perindopril
(therapeutic use)
- Pharmacogenetics
- Polymorphism, Single Nucleotide
(genetics)
- Receptor, Angiotensin, Type 1
(genetics)
- Receptor, Bradykinin B1
(genetics)
- Renin-Angiotensin System
(genetics)
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