Renin-Angiotensin System and Nitric Oxide Synthase Gene Polymorphisms in Relation to Stroke

Background: There is ample evidence that genetic factors contribute to cardiovascular disease risk. The present study aimed to assess the relation between polymorphisms of the angiotensin II type 1 receptor (AGTR1 A¹¹⁶⁶C) and endothelial nitric oxide synthase (NOS3 G⁸⁹⁴T) and the risk of stroke. Methods: We performed a case-cohort study on all first fatal and nonfatal stroke events (n = 74) and a 10% random sample (n = 1523) of a population-based cohort of women aged 49 to 70 years (n = 15,236; median follow-up 4.3 years). Univariate and multivariate unweigthed Cox proportional hazards regression models were used to assess the relation between the polymorphisms, their interactions with coexisting risk factors, and the risk of stroke. Results: The relation between the AGTR1 CC genotype and stroke risk (unadjusted hazards ratio [HR] 1.62; 95% confidence interval [CI], 0.81-3.28) was modified by increasing age (>56 years: adjusted HR 2.77; 95% CI, 1.17-6.56) and systolic blood pressure (BP) (>130 mm Hg: adjusted HR 2.58; 95% CI, 1.12-5.93). The NOS3 G⁸⁹⁴T polymorphism, however, was not associated with stroke risk. Conclusions: In the presence of other coexisting risk factors the AGTR1 A¹¹⁶⁶C but not the NOS3 G⁸⁹⁴T polymorphism increased the risk of stroke. The CC genotype may help identify those individuals who are at greatest risk and who may need (early) treatment or careful follow-up.