ORIGINAL ARTICLE Genetic variation in the renin-angiotensin system modifies the beneficial effects of ACE inhibitors on the risk of diabetes mellitus among hypertensives O ¨ Bozkurt 1 , WMM Verschuren 2 , BMA van Wieren-de Wijer 1 , MJ Knol 3 , A de Boer 1 , DE Grobbee 3 , MI Geerlings 3 , ER Heerdink 1 and OH Klungel 1 1 Faculty of Science, Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; 2 National Institute for Public Health and the Environment, Utrecht, The Netherlands and 3 Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands The aim of this study was to assess whether the association between angiotensin-converting enzyme (ACE) inhibitor use and the incidence of treated diabetes mellitus is modified by genetic polymorphisms in the renin-angiotensin system (RAS).In a nested case–con- trol study, treated hypertensive patients were genotyped for ACE (insertion (I)/deletion (D)), angiotensinogen (AGT; M235T) and angiotensin II type 1 receptor (AGTR1; A1166C). Cases of newly treated diabetes were identified based on pharmacy records and controls were not yet drug treated for diabetes (case:control ratio 1:10). Self-administered questionnaires and physical examinations were used to assess risk factors for diabetes mellitus. Logistic regression was used to calculate the relative risk of diabetes associated with ACE inhibitor use relative to other antihypertensive treatment, stratified by the RAS genotypes. Among 205 cases and 2050 controls, homozygous 1166A carriers of the AGTR1 gene had a significantly decreased incidence of diabetes associated with current use of ACE inhibitors (odds ratio, OR: 0.47; 95% CI: 0.26–0.84), whereas this incidence was increased among 1166C allele carriers (OR: 1.32; 95% CI: 0.81–2.14). The interaction OR was 3.21 (95% CI: 1.53–6.75). ACE I allele carriers had a significantly reduced incidence of diabetes associated with ACE inhibitors use (OR: 0.63; 95% CI: 0.41–0.98), whereas DD homozygotes had no reduced risk (OR: 0.95; 95% CI: 0.46–1.96). The risk of diabetes associated with ACE inhibitor use was not significantly modified by the AGT-M235T polymorphism. Treatment with ACE inhibitors in hypertensive subjects significantly reduces the occurrence of diabetes in homozygous 1166A carriers of the AGTR1 gene and carriers of the ACE I allele, but not in 1166C allele carriers of the AGTR1 gene and in homozygous ACE D allele carriers. Journal of Human Hypertension (2008) 22, 774–780; doi:10.1038/jhh.2008.62; published online 19 June 2008 Keywords: pharmacogenetics; ACE inhibitors; diabetes mellitus; RAS Introduction Essential hypertension is closely associated with type II diabetes mellitus. Both elevated blood pressure and impaired glucose tolerance are key components of the metabolic syndrome, a major cause of cardiovascular morbidity and mortality. 1 The metabolic effects of treatment with antihy- pertensive agents may be negative (diuretics, b-blockers), neutral (calcium antagonists) or positive (angiotensin-converting enzyme, ACE inhibitors and angiotensin II type 1 receptor blockers, ARBs). A recent meta-analysis assessed that the relative risk reduction of type II diabetes mellitus by ACE inhibitors or ARB therapy compared to diuretic therapy was 23 and 43%, respectively. 2 The me- chanisms through which ACE inhibitors and ARBs reduce the risk of diabetes mellitus remain uncer- tain, although several mechanisms, such as de- creased renal potassium wasting, and improved islet blood flow and pancreatic b-cell perfusion by reducing angiotensin II-mediated vasoconstriction in the pancreas, have been proposed. 3 Polymorph- isms in three genes that code for major components of the renin-angiotensin system (RAS), angiotensi- nogen (AGT) M235T, ACE insertion/deletion (I/D), and angiotensin II type 1 receptor (AGTR1) A1166C, Received 29 February 2008; revised 15 May 2008; accepted 20 May 2008; published online 19 June 2008 Correspondence: Dr OH Klungel, Faculty of Science, Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, Utrecht 3508 TB, The Netherlands. E-mail: o.h.klungel@uu.nl Journal of Human Hypertension (2008) 22, 774–780 & 2008 Macmillan Publishers Limited All rights reserved 0950-9240/08 $32.00 www.nature.com/jhh