title: Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project.
abstract: BACKGROUND
  Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unclear.
  
  
  OBJECTIVE
  To establish the magnitude of the vascular disease risk associated with an increased plasma homocysteine level and to examine interaction effects between elevated plasma homocysteine level and conventional risk factors.
  
  
  METHODS
  Case-control study.
  
  
  METHODS
  Nineteen centers in 9 European countries.
  
  
  METHODS
  A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years.
  
  
  METHODS
  Plasma total homocysteine was measured while subjects were fasting and after a standardized methionine-loading test, which involves the administration of 100 mg of methionine per kilogram and stresses the metabolic pathway responsible for the irreversible degradation of homocysteine. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate, serum cholesterol, smoking, and blood pressure were also measured.
  
  
  RESULTS
  The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loading identified an additional 27% of at-risk cases. A dose-response effect was noted between total homocysteine level and risk. The risk was similar to and independent of that of other risk factors, but interaction effects were noted between homocysteine and these risk factors; for both sexes combined, an increased fasting homocysteine level showed a more than multiplicative effect on risk in smokers and in hypertensive subjects. Red blood cell folate, cobalamin, and pyridoxal phosphate, all of which modulate homocysteine metabolism, were inversely related to total homocysteine levels. Compared with nonusers of vitamin supplements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels.
  
  
  CONCLUSIONS
  An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.
authors.affiliation: Department of Cardiology, Adelaide Hospital, Trinity College, Dublin, Ireland.
authors.forename: I M
authors.initials: IM
authors.lastname: Graham
authors.forename: L E
authors.initials: LE
authors.lastname: Daly
authors.forename: H M
authors.initials: HM
authors.lastname: Refsum
authors.forename: K
authors.initials: K
authors.lastname: Robinson
authors.forename: L E
authors.initials: LE
authors.lastname: Brattström
authors.forename: P M
authors.initials: PM
authors.lastname: Ueland
authors.forename: R J
authors.initials: RJ
authors.lastname: Palma-Reis
authors.forename: G H
authors.initials: GH
authors.lastname: Boers
authors.forename: R G
authors.initials: RG
authors.lastname: Sheahan
authors.forename: B
authors.initials: B
authors.lastname: Israelsson
authors.forename: C S
authors.initials: CS
authors.lastname: Uiterwaal
authors.forename: R
authors.initials: R
authors.lastname: Meleady
authors.forename: D
authors.initials: D
authors.lastname: McMaster
authors.forename: P
authors.initials: P
authors.lastname: Verhoef
authors.forename: J
authors.initials: J
authors.lastname: Witteman
authors.forename: P
authors.initials: P
authors.lastname: Rubba
authors.forename: H
authors.initials: H
authors.lastname: Bellet
authors.forename: J C
authors.initials: JC
authors.lastname: Wautrecht
authors.forename: H W
authors.initials: HW
authors.lastname: de Valk
authors.forename: A C
authors.initials: AC
authors.lastname: Sales Lúis
authors.forename: F M
authors.initials: FM
authors.lastname: Parrot-Rouland
authors.forename: K S
authors.initials: KS
authors.lastname: Tan
authors.forename: I
authors.initials: I
authors.lastname: Higgins
authors.forename: D
authors.initials: D
authors.lastname: Garcon
authors.forename: G
authors.initials: G
authors.lastname: Andria
mesh_terms: D000328:Adult; D001161:Arteriosclerosis / Q000097:blood* / Q000453:epidemiology*; D001774:Blood Chemical Analysis; D016022:Case-Control Studies; D005215:Fasting; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood; D006973:Hypertension / Q000097:blood; D016015:Logistic Models; D008297:Male; D008715:Methionine / Q000378:metabolism; D008875:Middle Aged; D012307:Risk Factors; D012907:Smoking / Q000097:blood; D014652:Vascular Diseases / Q000097:blood / Q000453:epidemiology
chemical_list: D006710:Homocysteine; D008715:Methionine