NOS3 polymorphisms, cigarette smoking, and cardiovascular disease risk: The Atherosclerosis Risk in Communities study

Craig R. Lee, Kari E. North, Molly S. Bray, Christy L. Avery, Mary Jane Mosher, David J. Couper, Josef Coresh, Aaron R. Folsom, Eric Boerwinkle, Gerardo Heiss, Darryl C. Zeldin

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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 ≥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.

Original languageEnglish (US)
Pages (from-to)891-899
Number of pages9
JournalPharmacogenetics and Genomics
Issue number12
StatePublished - Dec 2006


  • Coronary artery disease
  • Endothelial nitric oxide synthase
  • Polymorphism
  • Smoking
  • Stroke

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'NOS3 polymorphisms, cigarette smoking, and cardiovascular disease risk: The Atherosclerosis Risk in Communities study'. Together they form a unique fingerprint.

Cite this