title: MTRR 66A>G polymorphism in relation to congenital heart defects.
abstract: BACKGROUND
  Evidence is accumulating that periconceptional folic acid supplementation may prevent congenital heart defects (CHD). The methionine synthase reductase (MTRR) enzyme restores methionine synthase (MTR) enzyme activity and therefore plays an essential role in the folate- and vitamin B(12)-dependent remethylation of homocysteine to methionine. We studied the influence of the MTRR 66A>G polymorphism on CHD risk. In addition, possible interaction between this variant and plasma methylmalonic acid (MMA) concentrations, as an indicator of intracellular vitamin B(12) status, was investigated.
  
  
  METHODS
  Case-control and case-parental studies were conducted to explore this association. In total, 169 CHD patients and 213 child controls, and 159 mothers with a CHD-affected child and 245 female controls were included.
  
  
  RESULTS
  The maternal MTRR 66AG and GG vs. AA genotypes revealed an odds ratio (OR) of 1.3 (95% CI 0.72-2.20) and 1.3 (0.71-2.37), respectively. Family-based transmission disequilibrium analysis did not reveal a significant association of the foetal 66G allele with the development of a heart defect in children (chi(2)=2.94, p=0.086). Maternal 66GG genotype in combination with high MMA concentration (above the 80th percentile) was associated with a three-fold (OR 3.3, 95% CI 0.86-12.50) increased risk for all types of CHD in offspring.
  
  
  CONCLUSIONS
  These data indicate that maternal MTRR 66A>G polymorphism is not a risk factor for CHD. Maternal MTRR 66GG genotype with compromised vitamin B(12) status may possibly result in increased CHD risk. In addition to folate, vitamin B(12) supplementation may contribute to the prevention of CHD.
authors.affiliation: Children's Heart Centre, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. i.vanbeynum@cukz.umcn.nl
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: van Beynum
authors.forename: Margreet
authors.initials: M
authors.lastname: Kouwenberg
authors.forename: Livia
authors.initials: L
authors.lastname: Kapusta
authors.forename: Martin
authors.initials: M
authors.lastname: den Heijer
authors.forename: Ivon J M
authors.initials: IJ
authors.lastname: van der Linden
authors.forename: Otto
authors.initials: O
authors.lastname: Daniels
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood; D008875:Middle Aged; D009426:Netherlands; D009679:Nuclear Family; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors
chemical_list: D008764:Methylmalonic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase