Pharmacogenetic interactions of three candidate gene polymorphisms with ACE-inhibitors or beta-blockers and the risk of atherosclerosis.
OBJECTIVE
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 beta-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 >or= 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 (>or=4 years) beta-blocker treatment compared with no use of beta-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).


CONCLUSIONS
Overall, the risk of atherosclerosis in hypertensives taking a beta-blocker or ACE-inhibitor-based regimen was not strongly modified by any of the three candidate gene polymorphisms.
Schelleman
H
H
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Klungel
O H
OH
Witteman
J C M
JC
Hofman
A
A
van Duijn
C M
CM
de Boer
A
A
Stricker
B H Ch
BH
D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001161:Arteriosclerosis / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents