Pharmacogenetic interactions of three candidate gene polymorphisms with ACE‐inhibitors or β‐blockers and the risk of atherosclerosis

What is already known about this subject • To our knowledge, there are no prior studies which investigate whether there is a drug–gene interaction between the three genes involved in the renin–angiotensin system and ACE‐inhibitor therapy or β‐blocker therapy with these subclinical measurements of atherosclerosis. • Some studies have found an effect on blood pressure or stroke/myocardial infarction, although the results are not conclusive. What this study adds • The results do not indicate the presence of a strong drug–gene interaction between the use of ACE‐inhibitors or β‐blockers and the ACE insertion/deletion, AGT M235T or AGTR1573C/T polymorphism on the overall risk of atherosclerosis. Aims To investigate whether the angiotensin‐converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen M235T or angiotensin II receptor type 1 573C/T polymorphism modify the risk of atherosclerosis associated with β‐blocker or ACE‐inhibitor therapy. 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 of ≥ 55 years. In this study, 2216 subjects with hypertension were included. Three subclinical measurements were used for atherosclerosis, i.e. peripheral arterial disease, carotid atherosclerosis and aortic atherosclerosis. The interaction between antihypertensive drugs and genetic polymorphisms on the risk of atherosclerosis was determined with binary logistic regression analysis. Results The risk of aortic atherosclerosis associated with long‐term (≥4 years) β‐blocker treatment compared with no use of β‐blockers was higher in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene [synergy index (SI) = 3.36; 95% confidence interval (CI) 1.14, 9.97]. The risk of carotid atherosclerosis associated with long‐term ACE‐inhibitor treatment compared with no use of ACE‐inhibitors was lower in subjects with the TT genotype than in subjects with the MM genotype of the AGT gene (SI = 0.20; 95% CI 0.04, 0.95). Conclusion Overall, the risk of atherosclerosis in hypertensives taking a β‐blocker or ACE‐inhibitor‐based regimen was not strongly modified by any of the three candidate gene polymorphisms.