title: Prospective study of first stroke in relation to plasma homocysteine and MTHFR 677C>T and 1298A>C genotypes and haplotypes - evidence for an association with hemorrhagic stroke.
abstract: BACKGROUND
  Abnormalities in homocysteine metabolism have been suggested as risk factors for stroke. The aim of this prospective study was to examine whether total plasma homocysteine concentration (tHcy) and its main genetic determinant, methylene tetrahydrofolate reductase (MTHFR) polymorphisms, were associated with first ischemic or hemorrhagic stroke.
  
  
  METHODS
  This was a nested case-referent study of 321 ischemic and 60 hemorrhagic stroke cases, defined by WHO MONICA criteria and each matched with two event-free referents for sex, age, cohort, recruitment date and geographical area. All subjects were from the population-based Northern Sweden Health and Disease Study cohorts. Odds ratios were determined by conditional logistic regression.
  
  
  RESULTS
  The mean follow-up time was 4.2 years. Both tHcy and MTHFR were independent predictors of hemorrhagic stroke in multivariate models including body mass index, hypertension and, for MTHFR, tHcy [OR for the highest vs. lowest tHcy quartile 8.13 (95% CI 1.83-36.1), p(trend)=0.002; OR for MTHFR 677TT vs. 677CC genotype 3.62 (95% CI 0.77-17.0), p(trend)=0.040]. Haplotype analyses confirmed that the MTHFR 677T-1298A haplotype was positively associated with hemorrhagic stroke [OR 1.81 (95% CI 1.09-3.00), p=0.022], whereas the MTHFR 677C-1298C haplotype was not significantly related to either hemorrhagic or ischemic stroke. Neither tHcy nor the MTHFR polymorphisms were significant predictors of ischemic stroke.
  
  
  CONCLUSIONS
  Both elevated plasma homocysteine levels and the MTHFR 677T allele are indicators of increased risk of hemorrhagic stroke in the northern Swedish population.
authors.affiliation: Clinical Chemistry, Department of Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Hultdin
authors.forename: Bethany
authors.initials: B
authors.lastname: Van Guelpen
authors.forename: Anna
authors.initials: A
authors.lastname: Winkvist
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Lars
authors.initials: L
authors.lastname: Weinehall
authors.forename: Birgitta
authors.initials: B
authors.lastname: Stegmayr
authors.forename: Torbjörn K
authors.initials: TK
authors.lastname: Nilsson
mesh_terms: D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006470:Hemorrhage / Q000150:complications*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D020521:Stroke / Q000097:blood* / Q000150:complications / Q000235:genetics* / Q000628:therapy
chemical_list: D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)