Genetic and Pharmacogenetic Associations Between NOS3 Polymorphisms, Blood Pressure, and Cardiovascular Events in Hypertension

BACKGROUND: Polymorphisms in the endothelial nitric oxide synthase (NOS3) gene increase susceptibility to hypertension and cardiovascular disease. We examined genetic and pharmacogenetic associations between NOS3 polymorphisms, blood pressure (BP) control, and cardiovascular events in elderly, hypertensive coronary artery disease (CAD) patients. METHODS: Patients with CAD were randomly assigned to either verapamil SR- or atenolol-based antihypertensive treatment and followed for cardiovascular events. Cases (all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke) and an age-, sex-, race/ethnicity-matched control population were genotyped for the -786T>C and Glu298>Asp polymorphisms in NOS3. On-treatment BP and BP control were compared across genotype groups. Logistic regression was performed to estimate odds ratios (ORs) for the -786T>C and Glu298>Asp polymorphisms in the combined population and in randomized treatment groups. RESULTS: Genotype data were available for 256 cases and 769 controls. Among controls, mean on-treatment BP differed according to -786T>C genotype (T/T 137/78 mm Hg, T/C 133/76 mm Hg, C/C 133/75 mm Hg; P = 0.0007 for systolic, P = 0.09 for diastolic) which corresponded to differing rates of BP control (T/T 63%, T/C 72%, C/C 88%; P = 0.002). Neither polymorphisms was associated with case status, with or without regard to assigned treatment. CONCLUSIONS: The -786T>C, but not the Glu298>Asp variant of NOS3, may correlate with BP but do not appear to be associated with incident cardiovascular events in patients with established cardiovascular disease. The antihypertensive treatment approach did not appear to alter the genetic contribution to either BP control or cardiovascular events.