Thymidylate synthase repeat polymorphisms and risk of neural tube defects in a population from the northern United Kingdom

Craig S Wilding, Caroline L Relton, Matthew J Sutton, Pat A Jonas, Sally-Ann Lynch, E Janet Tawn, John Burn

Research output: Contribution to journalArticle (Academic Journal)peer-review

18 Citations (Scopus)


BACKGROUND: A 28-bp repeat polymorphism in the 5'UTR of the thymidylate synthase (TYMS) gene represents a candidate risk factor for neural tube defects (NTDs) due to involvement in folate-dependent homocysteine metabolism. Non-Hispanic, white, U.S. citizens carrying at least one 2x 28-bp repeat allele have recently been shown to be at a four-fold increased risk of spina bifida (SB). We investigated the association between this polymorphism and risk of NTD in families affected by NTDs and controls from the northern United Kingdom (UK).

METHODS: PCR was performed on genomic DNA extracted from blood or mouth swabs of family members affected by NTDs (mothers, fathers, and cases), and unaffected controls (mothers and infants) to determine the number of 28-bp repeat units within the promoter region of TYMS. Case-control and TDT analyses of the influence of TYMS genotype on risk of NTD, or NTD pregnancy, were conducted.

RESULTS: Odds ratio (OR) analysis indicated that individuals carrying the 2x 28-bp repeat allele either in homozygous or heterozygous form, are not at increased risk of NTDs, or of having an NTD affected pregnancy. Control population allele frequencies are seen to be markedly different between the U.S. controls and those in this study.

CONCLUSIONS: TYMS polymorphism appears to be not universally associated with NTD risk across Caucasian samples. The elevated risk of spina bifida in U.S. samples appears to be driven by an unusually low risk allele (2x 28 bp) frequency in control samples. Family based (TDT) testing of U.S. samples is therefore advocated.

Original languageEnglish
Pages (from-to)483-5
Number of pages3
Issue number7
Publication statusPublished - Jul 2004


  • Case-Control Studies
  • Fathers
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Great Britain
  • Humans
  • Male
  • Mothers
  • Neural Tube Defects
  • Polymorphism, Genetic
  • Repetitive Sequences, Nucleic Acid
  • Risk Factors
  • Thymidylate Synthase


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