Renin-angiotensin system polymorphisms and the association between use of angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors and the risk of diabetes

Introduction. We assessed the influence of genetic polymorphisms in the renin-angiotensin system on the risk of diabetes associated with the use of angiotensin II receptor blockers and angiotensin-converting enzyme (ACE) inhibitors. Materials and methods. We performed a matched case-control study among antihypertensive drug users. Pharmacy records and questionnaires were used to ascertain incident diabetes (cases), antihypertensive drug use, and risk factors. Controls did not (yet) have diabetes.We genotyped ACE (G4656C, which is in complete linkage disequilibrium with the ACE insertion/deletion polymorphism), angiotensinogen (M235T), and angiotensin II type 1 receptor (A1166C). Results. Among 495 cases of incident diabetes and 2,624 controls, homozygous 1166C carriers of angiotensin II type 1 receptor who used angiotensin II receptor blockers had an increased risk of diabetes compared to 1166A carriers (interaction odds ratio 5.3 [95% confidence interval: 1.8-16.1]). Homozygous ACE GG subjects who used ACE inhibitors ≥ 1 defined daily dose/day had a higher risk of diabetes compared to subjects with the ACE C allele (interaction odds ratio 2.3 [95% confidence interval: 1.2-4.5]). Conclusions. Angiotensin II receptor blockers increase the occurrence of diabetes in homozygous 1166C carriers of angiotensin II type 1 receptor, but not in 1166A carriers. ACE inhibitors at doses ≥ 1 defined daily dose/day increase the risk of diabetes among homozygous ACE GG carriers, but not in 4656C carriers.