The 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.
We 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.
Although 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.
The 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.
aDepartment of Epidemiology & Biostatistics
cDepartment of Internal Medicine
dDepartment of Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands
bInspectorate for Healthcare, The Hague, The Netherlands
eDepartment of Clinical Pharmacology, University of Groningen, Groningen, The Netherlands
Correspondence and requests for reprints to Dr B.H.Ch. Stricker, Pharmaco-epidemiology Unit, Department of Epidemiology & Biostatistics, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, the Netherlands
Tel: +31-10-4088294; fax: +31-10-4089382;
Received 3 March 2004 Accepted 12 October 2004