Thymidylate synthase polymorphisms and risk of conotruncal heart defects

Am J Med Genet A. 2012 Sep;158A(9):2194-203. doi: 10.1002/ajmg.a.35310. Epub 2012 Aug 7.


In this study, we investigated whether the two TYMS functional variants (28 bp VNTR and 1494del6) (275 cases and 653 controls) and six selected SNPs (265 case infants, 535 control infants; 169 case mothers and 276 control mothers) were associated with risks of conotruncal heart defects. Further, we evaluated interaction effects between these gene variants and maternal folate intake for risk of CTD. Cases with diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. DNA samples were collected using buccal brushes or drawn from the repository of newborn screening blood specimens when available. Genetic variants were treated as categorical variables (homozygous referent, heterozygote, homozygous variant). Odds ratios and 95% confidence intervals (CI) were computed to estimate risks among all subjects, Hispanic and non-Hispanic whites, respectively, using logistic regression. Gene-folate interactions were assessed for these variants by adding an interaction term to the logistic model. A dichotomized composite variable, "combined folate intake," was created by combining maternal peri-conceptional use of folic acid-containing vitamin supplements with daily dietary intake of folate. In general, the results do not show strong gene-only effects on risk of CTD. We did, however, observe a 3.6-fold increase in CTD risk (95% CI: 1.1-11.9) among infants who were homozygotes for the 6 bp deletion in the 3'-untranslated region (UTR) (1694del6) and whose mothers had low folate intake during the peri-conceptional period.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Case-Control Studies
  • DNA Primers
  • Heart Defects, Congenital / enzymology
  • Heart Defects, Congenital / genetics*
  • Humans
  • Infant, Newborn
  • Polymerase Chain Reaction
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Thymidylate Synthase / genetics*


  • DNA Primers
  • Thymidylate Synthase