NOS3 polymorphisms, cigarette smoking, and cardiovascular disease risk: the Atherosclerosis Risk in Communities study.
OBJECTIVE
Endothelial nitric oxide synthase (NOS3) activity and cigarette smoking significantly influence endothelial function. We sought to determine whether cigarette smoking modified the association between NOS3 polymorphisms and risk of coronary heart disease or stroke.


METHODS
All 1085 incident coronary heart disease cases, all 300 incident ischemic stroke cases, and 1065 reference individuals from the Atherosclerosis Risk in Communities study were genotyped for the T-786C and E298D polymorphisms in NOS3. Using a case-cohort design, associations between genotype/haplotype and disease risk were evaluated by multivariable proportional hazards regression. Multiplicative scale interaction testing evaluated the influence of cigarette smoking history at baseline on these associations.


RESULTS
In Caucasians, association between E298D genotype and risk of coronary heart disease was significantly modified by current smoking status (interaction P=0.013), with the highest risk observed in smokers carrying the variant D298 allele relative to nonsmokers carrying two E298 alleles (adjusted hazard rate ratio 2.07, 95% confidence interval 1.39-3.07). In African-Americans, association between T-786C genotype and risk of ischemic stroke was significantly modified by pack-year smoking history (interaction P=0.037), with the highest risk observed in >or=20 pack-year smokers carrying the variant C-786 allele relative to <20 pack-year smokers carrying two T-786 alleles (adjusted hazard rate ratio 4.03, 95% confidence interval 1.54-10.6).


CONCLUSIONS
An interaction between the E298D and T-786C polymorphisms in NOS3, cigarette smoking, and risk of incident coronary heart disease and ischemic stroke events appears to exist, suggesting a potential complex interplay between genetic and environmental factors and cardiovascular disease risk.
Lee
Craig R
CR
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27709, USA.
North
Kari E
KE
Bray
Molly S
MS
Avery
Christy L
CL
Mosher
Mary Jane
MJ
Couper
David J
DJ
Coresh
Josef
J
Folsom
Aaron R
AR
Boerwinkle
Eric
E
Heiss
Gerardo
G
Zeldin
Darryl C
DC
D001741:Black or African American / Q000235:genetics; D000483:Alleles; D001483:Base Sequence; D002318:Cardiovascular Diseases / Q000201:enzymology* / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D015331:Cohort Studies; D003327:Coronary Disease / Q000201:enzymology / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D020521:Stroke / Q000201:enzymology / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
D017931:DNA Primers; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III