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Background and Purpose —Essential hypertension is a significant risk factor for stroke. Genes contributing to interindividual variation in blood pressure levels and essential hypertension status may play a role in the etiology of stroke either through their effects on blood pressure levels or through separate pathways. For this reason, we sought to examine the association between the α-adducin (ADD1 ) G/W460 and G-protein β3 subunit (GNβ3 ) 825C/T polymorphisms and subclinical and clinical stroke in the Atherosclerosis Risk in Communities (ARIC) Study.Methods —Subclinical stroke was determined by cerebral MRI. Subclinical cerebral infarct cases (n=202) were compared with a stratified random sample (MRI-CRS) identified from individuals participating in the MRI examination (n=211). Incidence of clinical ischemic stroke was determined by following the ARIC cohort for an average of 7.2 years for potential cerebrovascular events; 231 validated clinical ischemic strokes were identified. A stratified random sample of the ARIC cohort (CRS) (n=984) was used as the comparison group for the clinical cases.Results —The frequency of theADD1 W460 allele was determined for the subclinical cases (0.12), MRI-CRS (0.16), clinical cases (0.14), and CRS (0.17). The frequency of theGNβ3 825T allele was determined in whites and blacks, respectively, for the subclinical cases (0.26, 0.73), MRI-CRS (0.31, 0.75), clinical cases (0.36, 0.72), and CRS (0.30, 0.72). TheADD1 W460 and GNβ3 825T alleles were not significantly associated with subclinical stroke. TheADD1 W460 allele was also not a significant predictor of clinical stroke. TheGNβ3 825T allele was significantly associated with clinical stroke in whites after adjustment for age and sex (hazard rate ratio, 1.45; 95% CI, 1.05 to 2.00) and after further adjustment for multiple stroke risk factors (hazard rate ratio, 1.68; 95% CI, 1.18 to 2.41). TheGNβ3 825T allele was not significantly associated with clinical stroke in blacks for either adjustment model.Conclusions —TheGNβ3 gene 825C/T polymorphism is significantly associated with incident clinical ischemic stroke in a white middle-aged American population, but not in blacks. This association does not appear to be mediated by established stroke risk factors, specifically blood pressure levels or hypertension status.

G-Protein β3 Subunit and α-Adducin Polymorphisms and Risk of Subclinical and Clinical Stroke