title: Lack of evidence of association between MTHFR C677T polymorphism and congenital heart disease in a TDT study design.
abstract: BACKGROUND
  Hyperhomocysteinemia is frequently associated with congenital defects of the heart and neural tube. A common missense mutation in the MTHFR gene (C to T substitution at position 677 changing valine to alanine) produces a variant with reduced enzymatic action, resulting in higher plasma levels of homocysteine. The aim of this study is to investigate whether MTHFR C677T functional genetic variant is associated with an increased risk of congenital heart disease (CHD) development using a family-based case-control design and the Transmission Disequilibrium Test (TDT) approach.
  
  
  METHODS
  We selected 91 consecutive patients with congenital heart disease for the study. From these patients we were able to obtain samples on 147 parents. The C677T polymorphism at the MTHFR gene was determined from each participant.
  
  
  RESULTS
  A statistically significant association was disclosed in univariate analysis using a family-based case-control design (p<0.0001 assuming an additive genetic model, p<0.0001 assuming a dominant genetic model, and p=0.01 assuming a recessive genetic model). This association was explained by an increased frequency of the T allele in patients as compared to their fathers. However, by using a TDT approach a highly non-significant result was obtained and no association could be defined between this locus and congenital heart disease.
  
  
  CONCLUSIONS
  We did not find sufficient evidence for an association between MTHFR C677T genotype and congenital heart disease in our study group. Previous reports on such association may be due to population genetic structure.
authors.affiliation: Laboratory of Genetics and Molecular Cardiology, Heart Institute, São Paulo University Medical School, São Paulo, Brazil. lbmpereira@incor.usp.br
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Pereira
authors.forename: José
authors.initials: J
authors.lastname: Xavier-Neto
authors.forename: Sônia M
authors.initials: SM
authors.lastname: Mesquita
authors.forename: Glória F A
authors.initials: GF
authors.lastname: Mota
authors.forename: Antônio Augusto
authors.initials: AA
authors.lastname: Lopes
authors.forename: José Eduardo
authors.initials: JE
authors.lastname: Krieger
mesh_terms: D000465:Algorithms; D000483:Alleles; D001938:Brazil; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D003327:Coronary Disease / Q000196:embryology / Q000235:genetics; D003430:Cross-Sectional Studies; D005192:Family Health; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006330:Heart Defects, Congenital / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2)