title: Transcobalamin 2 variant associated with poststroke homocysteine modifies recurrent stroke risk.
abstract: OBJECTIVE
  The Vitamin Intervention for Stroke Prevention trial found an association between baseline poststroke homocysteine (Hcy) and recurrent stroke. We investigated genes for enzymes and cofactors in the Hcy metabolic pathway for association with Hcy and determined whether associated single nucleotide polymorphisms (SNPs) influenced recurrent stroke risk.
  
  
  METHODS
  Eighty-six SNPs in 9 candidate genes (BHMT1, BHMT2, CBS, CTH, MTHFR, MTR, MTRR, TCN1, and TCN2) were genotyped in 2,206 subjects (83% European American). Associations with Hcy measures were assessed using linear regression models assuming an additive genetic model, adjusting for age, sex, and race and additionally for baseline Hcy when postmethionine load change was assessed. Associations with recurrent stroke were evaluated using survival analyses.
  
  
  RESULTS
  Five SNPs in the transcobalamin 2 (TCN2) gene were associated with baseline Hcy (false discovery rate [FDR]-adjusted p = 0.049). TCN2 SNP rs731991 was associated with recurrent stroke risk in the low-dose arm of the trial under a recessive model (log-rank test p = 0.009, hazard ratio 0.34). Associations with change in postmethionine load Hcy levels were found with 5 SNPs in the cystathionine β-synthase (CBS) gene (FDR-adjusted p < 0.031).
  
  
  CONCLUSIONS
  TCN2 variants contribute to poststroke Hcy levels, whereas variants in the CBS gene influence Hcy metabolism. Variation in the TCN2 gene also affects recurrent stroke risk in response to cofactor therapy.
authors.affiliation: Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
authors.forename: F-C
authors.initials: FC
authors.lastname: Hsu
authors.forename: E G
authors.initials: EG
authors.lastname: Sides
authors.forename: J C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: B B
authors.initials: BB
authors.lastname: Worrall
authors.forename: G A
authors.initials: GA
authors.lastname: Elias
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: W-M
authors.initials: WM
authors.lastname: Chen
authors.forename: B M
authors.initials: BM
authors.lastname: Coull
authors.forename: J F
authors.initials: JF
authors.lastname: Toole
authors.forename: S S
authors.initials: SS
authors.lastname: Rich
authors.forename: K L
authors.initials: KL
authors.lastname: Furie
authors.forename: M M
authors.initials: MM
authors.lastname: Sale
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D056726:Genetic Association Studies; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020521:Stroke / Q000097:blood* / Q000235:genetics*; D014155:Transcobalamins / Q000235:genetics*
chemical_list: D014155:Transcobalamins; D006710:Homocysteine