Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide.
BACKGROUND
Pharmacogenetic discoveries may enable greater individualization of antihypertensive drug therapy. We investigated polymorphisms in the genes encoding endothelial nitric oxide synthase (Glu298-->Asp), alpha-adducin (Gly460-->Trp), the beta(1)-adrenoceptor (Arg389-->Gly), beta2-adrenoceptor (Arg16-->Gly), and lipoprotein lipase (Ser447-->Stop) for their potential influences on blood pressure (BP) response to a thiazide diuretic.


METHODS
The sample consisted of 291 unrelated non-Hispanic African American adults (150 women and 141 men) and 294 unrelated non-Hispanic white adults (126 women and 168 men) who were between 30 and 59.9 years of age and who had essential hypertension. Previous antihypertensive drug therapy was withdrawn for at least 4 weeks, and subjects were then treated with hydrochlorothiazide (25 mg daily) for 4 weeks to determine BP response.


RESULTS
The covariates of ethnicity, gender, age, and waist-to-hip ratio accounted for 26% of interindividual variation in systolic BP response and 11% of interindividual variation in diastolic BP response. After adjustment for covariates, the endothelial nitric oxide synthase Glu298-->Asp polymorphism made an additional statistically significant contribution to predicting diastolic BP response to hydrochlorothiazide, accounting for another 1% of interindividual variation in response (P =.034). In contrast, the other polymorphisms, including the alpha-adducin Gly460-->Trp polymorphism, made no statistically significant contributions to prediction of BP response.


CONCLUSIONS
Although we reject the null hypothesis of no genetic effects on BP response to hydrochlorothiazide, the influence of variation at single sites is likely to be small. More extensive characterization of genetic variation is required for pharmacogenetic approaches to become clinically useful in tailoring antihypertensive drug therapy for individual patients.
Turner
Stephen T
ST
Division of Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. turner.stephen@mayo.edu
Chapman
Arlene B
AB
Schwartz
Gary L
GL
Boerwinkle
Eric
E
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D004232:Diuretics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D011110:Polymorphism, Genetic; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use*; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D004232:Diuretics; D006852:Hydrochlorothiazide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D049993:Sodium Chloride Symporter Inhibitors; D000099291:Adducins; C496314:NOS3 protein, human