Angiotensinogen Met235Thr polymorphism, angiotensin-converting enzyme inhibitor therapy, and the risk of nonfatal stroke or myocardial infarction in hypertensive patients.
The ThrThr genotype of the angiotensinogen (AGT) Met235Thr polymorphism has been associated with elevated AGT levels, hypertension, increased heart disease risk, and improved blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitors. We hypothesized that risk of stroke or myocardial infarction (MI) associated with ACE inhibitor use varies by AGT genotype, with a larger protective effect of ACE inhibitors in individuals with the ThrThr genotype than individuals who are carriers of the Met allele.


METHODS
We conducted a population-based case-control study. Participants were health maintenance organization members aged 30 to 79 years with treated hypertension. Those who survived incident stroke (n = 116) or MI (n = 208) during the study period were designated as cases. Control subjects (n = 717) were randomly sampled and frequency-matched to MI cases on age, sex, and calendar year. Health history, medication use, and AGT genotype were assessed.


RESULTS
ThrThr genotype was present in 21% of stroke cases, 26% of MI cases, and 19% of control subjects. Compared with nonuse, ACE inhibitor use was associated with lower stroke risk among Thr homozygotes (odds ratio [OR] = 0.37, 95% CI = 0.14 to 0.99) than among Met carriers (OR = 1.4, 95% CI = 0.88 to 2.4; P for interaction =.02). Compared with nonuse, ACE inhibitor use was associated with similar MI risk among Thr homozygotes (OR = 0.90, 95% CI = 0.62 to 1.3) and among Met carriers (OR = 1.2, 95% CI = 0.60 to 2.5; P for interaction = 0.5).


CONCLUSIONS
In this hypertensive population, the association of ACE inhibitor use with risk of nonfatal stroke varied by genotype. The protective association between ACE inhibitor use and nonfatal stroke risk among individuals with ThrThr genotype was not observed for nonfatal MI.
Bis
Joshua C
JC
Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, Washington 98101, USA. joshbis@u.washington.edu
Smith
Nicholas L
NL
Psaty
Bruce M
BM
Heckbert
Susan R
SR
Edwards
Karen L
KL
Lemaitre
Rozenn N
RN
Lumley
Thomas
T
Rosendaal
Frits R
FR
D000328:Adult; D000368:Aged; D000483:Alleles; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000808:Angiotensinogen / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012306:Risk; D020521:Stroke / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000808:Angiotensinogen