NAT1, NOS3, and TYMS genotypes and the risk of conotruncal cardiac defects

Birth Defects Res A Clin Mol Teratol. 2011 Jan;91(1):61-5. doi: 10.1002/bdra.20745. Epub 2010 Dec 1.


Background: Although congenital heart defects (CHDs) are a common and serious group of birth defects, relatively little is known about the causes of these conditions, and there are no established prevention strategies. There is, however, evidence suggesting that the risk of CHDs in general, and conotruncal and related defects (CTRDs) in particular, may be associated with maternal folate status and genetic variants of folate-related genes. Although several folate-related genes have been studied as they relate to CHDs and CTRDs (e.g., MTHFR), others have not been adequately assessed.

Methods: Case-parent triads were examined using log-linear analyses to assess the associations between CTRDs and both the genotype inherited by the case and the maternal genotype for the following variants: NAT1 1095C>A, NOS3 894G>T, and TYMS 1494del6. Subgroup analyses were also conducted among cases with classic conotruncal defects and cases with normally related great arteries.

Results: The results provided little evidence that CTRD risk was associated with the genotype inherited by the case for any of the analyzed variants. However, our results suggest that CTRD risk may be associated with the maternal genotype for NOS3 894G>T (p = 0.024 in the subgroup with normally related great arteries) and TYMS 1494del6 (p = 0.048 in the subgroup with classic conotruncal defects). However, these results were not significant after correcting for multiple comparisons.

Conclusion: This study provides further evidence that CTRD risk may be related to variation within folate-pathway genes and suggests that these associations are, at least in part, mediated through the maternal genotype.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Arylamine N-Acetyltransferase / genetics
  • Female
  • Folic Acid / metabolism*
  • Genetic Predisposition to Disease*
  • Genotype
  • Heart Defects, Congenital / genetics
  • Humans
  • Isoenzymes / genetics
  • Male
  • Nitric Oxide Synthase Type III / genetics*
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Thymidylate Synthase / genetics*


  • Isoenzymes
  • Folic Acid
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • Thymidylate Synthase
  • Arylamine N-Acetyltransferase
  • N-acetyltransferase 1

Supplementary concepts

  • Conotruncal cardiac defects