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BackgroundThe response to angiotensin-I converting enzyme (ACE)-inhibitor therapy is highly variable. Residual ACE activity during treatment, potentially modified by the ACE insertion/deletion (I/D) polymorphism, may explain part of this variability. We studied the possible interaction between ACE-inhibitor therapy in patients with hypertension and the ACE I/D polymorphism in incident heart failure and death.MethodsWe studied 3365 hypertensive participants of the population-based Rotterdam Study, without heart failure at baseline for whom ACE-genotyping was successful. Incident heart failure was defined according to established criteria. In addition, total and cardiovascular mortality were studied as endpoints. A Cox regression model with use of ACE-inhibitors defined as time-dependent covariates was used for data-analysis. Interaction was tested in this model assuming an allele-effect relationship.ResultsAlthough we could not demonstrate a beneficial effect of ACE-inhibitors, there was significant interaction between the ACE I/D polymorphism (II-ID-DD) and ACE-inhibitor use in the prediction of total and cardiovascular mortality. Mortality risk associated with treatment increased with the number of D alleles present; e.g. for total mortality in the II genotype group: RR=0.95 (95% CI 0.63-1.45), in the ID genotype group: RR=1.08 (95% CI 0.84-1.38) and in the DD genotype group: RR=1.61 (95% CI 1.18-2.18). No statistically significant interaction was found for incident heart failure.ConclusionThe results of our study suggest a relative resistance to ACE-inhibitor therapy in subjects with hypertension and the DD genotype compared to the II genotype, with the ID genotype in an intermediate position.

Original publication




Journal article


Pharmacogenetics and genomics

Publication Date





75 - 81


Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.


Humans, Hypertension, Peptidyl-Dipeptidase A, Angiotensin-Converting Enzyme Inhibitors, Proportional Hazards Models, Risk, Prospective Studies, Gene Deletion, Genotype, Polymorphism, Genetic, Alleles, Aged, Middle Aged, Female, Male