title: Genetic evidence that nitric oxide modulates homocysteine: the NOS3 894TT genotype is a risk factor for hyperhomocystenemia.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, 153 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104-6084, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Brown
authors.forename: Leo A J
authors.initials: LA
authors.lastname: Kluijtmans
authors.forename: Ian S
authors.initials: IS
authors.lastname: Young
authors.forename: Jayne
authors.initials: J
authors.lastname: Woodside
authors.forename: John W G
authors.initials: JW
authors.lastname: Yarnell
authors.forename: Dorothy
authors.initials: D
authors.lastname: McMaster
authors.forename: Liam
authors.initials: L
authors.lastname: Murray
authors.forename: Alun E
authors.initials: AE
authors.lastname: Evans
authors.forename: Colin A
authors.initials: CA
authors.lastname: Boreham
authors.forename: Helene
authors.initials: H
authors.lastname: McNulty
authors.forename: J J
authors.initials: JJ
authors.lastname: Strain
authors.forename: Laura E
authors.initials: LE
authors.lastname: Mitchell
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Whitehead
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D009660:Northern Ireland / Q000453:epidemiology; D017354:Point Mutation; D011446:Prospective Studies; D012307:Risk Factors; D014805:Vitamin B 12 / Q000097:blood
chemical_list: D006710:Homocysteine; D009569:Nitric Oxide; D005492:Folic Acid; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12