Diuretic-gene interaction and the risk of myocardial infarction and stroke.
This study investigates whether the interaction between diuretics and alpha-adducin (ADD1) G460W or G-protein beta3-subunit (GNB3) rs2301339 polymorphism modifies the risk of myocardial infarction (MI) or stroke. Data were used from the Rotterdam Study. The drug-gene interaction was determined with a Cox proportional hazard model with adjustment for each drug class as time-dependent covariates. The risk of MI in current users of low-ceiling diuretics with one or two copies of the ADD1 W-allele (hazard ration (HR)=0.92) was similar compared to the expected joint effect of the W-allele and low-ceiling diuretics on a multiplicative scale (1.04 x 0.90=0.94) (synergy index (SI):0.99; 95% confidence interval (CI): 0.43-2.27). No drug-gene interaction was found on the risk of stroke (SI:0.66; 95% CI:0.43-1.27). In addition, a trend towards an interaction was found between current use and the GNB3 rs230119 G/A polymorphism on the risk of MI (SI: 0.51; 95% CI: 0.23-1.15), whereas no interaction on the risk of stroke was found (SI: 0.84; 95% CI: 0.46-1.56).
Schelleman
H
H
Department of Epidemiology & Biostatistics, Erasmus MC, Rotterdam, The Netherlands.
Klungel
O H
OH
Witteman
J C M
JC
Breteler
M M B
MM
Hofman
A
A
van Duijn
C M
CM
de Boer
A
A
Stricker
B H Ch
BH
D000368:Aged; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D004232:Diuretics / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000139:chemically induced* / Q000235:genetics*; D009426:Netherlands; D011110:Polymorphism, Genetic; D011159:Population Surveillance; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000139:chemically induced* / Q000235:genetics*; D013997:Time Factors; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D004232:Diuretics; D020962:Heterotrimeric GTP-Binding Proteins; D000099291:Adducins; C454420:G-protein beta3 subunit