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Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1014-1020
Published online before print April 10, 2003, doi: 10.1161/01.ATV.0000071348.70527.F4
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1014.)
© 2003 American Heart Association, Inc.

Vascular Biology

Genetic Evidence That Nitric Oxide Modulates Homocysteine

The NOS3 894TT Genotype Is a Risk Factor for Hyperhomocystenemia

Karen S. Brown; Leo A.J. Kluijtmans; Ian S. Young; Jayne Woodside; John W.G. Yarnell; Dorothy McMaster; Liam Murray; Alun E. Evans; Colin A. Boreham; Helene McNulty; J.J. Strain; Laura E. Mitchell; Alexander S. Whitehead

From the Department of Pharmacology and Center for Pharmacogenetics (K.S.B., A.S.W.), University of Pennsylvania School of Medicine, Philadelphia, Pa; Laboratory of Pediatrics and Neurology (L.A.J.K.), University Medical Center Nijmegen, The Netherlands; Cardiovascular Research Centre (I.S.Y., J.W., J.W.G.Y., D.M., L.M.) and Department of Epidemiology and Public Health (A.E.), Queen’s University Belfast, Northern Ireland; Northern Ireland Centre for Diet and Health (C.A.B., H.M., J.J.S.), University of Ulster, Coleraine, Northern Ireland; and Texas A&M University System Health Science Center (L.E.M.), Institute of Biosciences and Technology, Houston, Tex.

Correspondence to Alexander S. Whitehead, DPhil, Department of Pharmacology, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084. E-mail aswhitehead{at}pharm.med.upenn.edu

Objective— Mild hyperhomocystenemia is an independent, graded risk factor for cardiovascular disease. Genetic determinants of hyperhomocystenemia include functional polymorphisms in several folate/homocysteine metabolic enzymes. Nitric oxide may also modulate plasma homocysteine (tHcy) concentrations, either by direct inhibition of methionine synthase or via an indirect effect on folate catabolism.

Methods and Results— The hypothesis that the endothelial nitric oxide synthase (NOS3) G894T polymorphism is a genetic determinant of tHcy concentrations was tested in 2 independent healthy adult populations. In both populations, NOS3 genotype was significantly associated with tHcy concentrations in nonsmokers with low folate (P=0.03 for each). Models were constructed to adjust for known determinants of tHcy concentrations and test for interactions between NOS3 genotype and these determinants in nonsmokers from each population. NOS3 genotype remained a significant determinant of tHcy concentrations after adjustment. Interactions between NOS3 genotype and serum folate were significant in both populations, and the interaction between NOS3 genotype and MTHFR C677T genotype was significant in the larger population.

Conclusions— These data indicate that the NOS3 894TT genotype is a risk factor for elevated tHcy in healthy nonsmoking adults with low serum folate and supports the hypothesis that nitric oxide modulates homocysteine through an effect on folate catabolism.


Key Words: nitric oxide • nitric oxide synthase • hyperhomocystenemia • 5,10-methylenetetrahydrofolate reductase • smoking




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