G-protein beta3 subunit and alpha-adducin polymorphisms and risk of subclinical and clinical stroke.
OBJECTIVE
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 alpha-adducin (ADD1) G/W460 and G-protein beta3 subunit (GNbeta3) 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 the ADD1 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 the GNbeta3 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). The ADD1 W460 and GNbeta3 825T alleles were not significantly associated with subclinical stroke. The ADD1 W460 allele was also not a significant predictor of clinical stroke. The GNbeta3 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). The GNbeta3 825T allele was not significantly associated with clinical stroke in blacks for either adjustment model.


CONCLUSIONS
The GNbeta3 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.
Morrison
A C
AC
Human Genetics Center, University of Texas-Houston Health Science Center, Institute of Molecular Medicine, Houston, Texas, USA.
Doris
P A
PA
Folsom
A R
AR
Nieto
F J
FJ
Boerwinkle
E
E
D017677:Age Distribution; D000483:Alleles; D044383:Black People / Q000235:genetics; D002545:Brain Ischemia / Q000175:diagnosis / Q000453:epidemiology; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D015897:Comorbidity; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D021122:Protein Subunits; D018570:Risk Assessment; D012307:Risk Factors; D017678:Sex Distribution; D020521:Stroke / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics; D001741:Black or African American; D000099291:Adducins
D002148:Calmodulin-Binding Proteins; D020962:Heterotrimeric GTP-Binding Proteins; D021122:Protein Subunits; D000099291:Adducins