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HYPERTENSION

Drug–Gene Interaction Between the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene and Antihypertensive Therapy

PhD Candidate, Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, Netherlands; Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands

Olaf H Klungel, PharmD PhD

Associate Professor, Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences

Cornelia M van Duijn, PhD

Professor, Department of Epidemiology & Biostatistics, Erasmus MC

Jacqueline CM Witteman, PhD

Associate Professor, Department of Epidemiology & Biostatistics, Erasmus MC

Albert Hofman, MD PhD

Professor, Department of Epidemiology & Biostatistics, Erasmus MC

Anthonius de Boer, MD PhD

Professor, Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences

Bruno HCh Stricker, PhD

Professor, Department of Epidemiology & Biostatistics, Erasmus MC

Reprints: Dr. Stricker, Department of Epidemiology & Biostatistics, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, Netherlands, fax 00 31 104089382, b.stricker{at}erasmusmc.nl

BACKGROUND: Despite the availability of a variety of effective drugs, inadequate control of blood pressure is common. There are some indications that the angiotensin-converting enzyme (ACE) gene modifies the response to antihypertensive drugs, but the results have been inconclusive.

OBJECTIVE: To investigate whether the insertion/deletion polymorphism of the ACE gene modifies blood pressure differences among subjects using diuretics, ß-blockers, calcium-channel antagonists, or ACE inhibitors.

METHODS: Data were used from the Rotterdam Study, a population-based, prospective, cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or older. Data from 3 subsequent cross-sectional investigations were used, as well. Subjects were included if they had high blood pressure during one or more examinations and/or used monotherapy with a diuretic, ß-blocker, calcium-channel antagonist, or ACE inhibitor. A marginal, generalized, linear model was used to assess the association between the mean difference in systolic/diastolic blood pressure and antihypertensive classes stratified by the 3 genotypes.

RESULTS: In total, 3025 hypertensive individuals were included, and 6500 measurements of blood pressure were taken. The percentages of DD, ID, and II genotypes were 28.3%, 51.4%, and 20.3%, respectively. The mean differences in systolic blood pressure between the II and DD genotypes were 0.23 mm Hg (95% CI –5.48 to 5.94) for diuretics, –2.41 mm Hg (95% CI –6.72 to 1.90) for ß-blockers, 2.12 mm Hg (95% CI –4.64 to 8.89) for calcium-channel antagonists, and –2.01 mm Hg (95% CI –9.82 to 5.79) for ACE inhibitors.

CONCLUSIONS: The adjusted mean difference in diastolic and systolic blood pressure among diuretic, ß-blocker, calcium-channel antagonist, or ACE inhibitor users was not modified by the ACE insertion/deletion polymorphism.

Key Words: angiotensin-converting enzyme gene, polymorphism

Published Online, January 31, 2006. www.theannals.com, DOI 10.1345/aph.1G316