Evaluation of heterogeneity in the association between congenital heart defects and variants of folate metabolism genes: conotruncal and left-sided cardiac defects

Birth Defects Res A Clin Mol Teratol. 2011 Oct;91(10):879-84. doi: 10.1002/bdra.22849. Epub 2011 Aug 24.


Background: Genetic variation in the folate metabolic pathway may influence the risk of congenital heart defects. This study was undertaken to assess the associations between the inherited and maternal genotypes for variants in folate-related genes and the risk of a composite heart phenotype that included two component phenotypes: conotruncal heart defects (CTDs) and left-sided cardiac lesions (LSLs).

Methods: Nine folate-related gene variants were evaluated using data from 692 case-parent triads (CTD, n = 419; LSL, n = 273). Log-linear analyses were used to test for heterogeneity of the genotype-phenotype association across the two component phenotypes (i.e., CTD and LSLs) and, when there was no evidence of heterogeneity, to assess the associations of the maternal and inherited genotypes with the composite phenotype.

Results: There was little evidence of heterogeneity of the genotype-phenotype association across the two component phenotypes or of an association between the genotypes and the composite phenotype. There was evidence of heterogeneity in the association of the maternal MTR A2756G genotype (p = 0.01) with CTDs and LSLs. However, further analyses suggested that the observed associations with the maternal MTR A2756G genotype might be confounded by parental imprinting effects.

Conclusions: Our analyses of these data provide little evidence that the folate-related gene variants evaluated in this study influence the risk of this composite congenital heart defect phenotype. However, larger and more comprehensive studies that evaluate parent-of-origin effects, as well as additional folate-related genes, are required to more fully explore the relation between folate and congenital heart defects.

Publication types

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

MeSH terms

  • Female
  • Folic Acid / genetics*
  • Folic Acid / metabolism*
  • Genetic Predisposition to Disease
  • Genotype*
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / metabolism*
  • Humans
  • Male
  • Risk Factors


  • Folic Acid