Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population

Anne Parle-McDermott, Peadar N. Kirke, James L. Mills, Anne M. Molloy, Christopher Cox, Valerie B. O'Leary, Faith Pangilinan, Mary Conley, Laura Cleary, Lawrence C. Brody, John M. Scott

Research output: Contribution to journalArticlepeer-review

Abstract

The risk of neural tube defects (NTDs) is known to have a significant genetic component that could act through either the NTD patient and/or maternal genotype. The success of folic acid supplementation in NTD prevention has focused attention on polymorphisms within folate-related genes. We previously identified the 1958>A (R653Q) polymorphism of the trifunctional enzyme MTHFD1 (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase; often referred to as 'C1 synthase') as a maternal risk for NTDs, but this association remains to be verified in a separate study to rule out a chance finding. To exclude this possibility, we genotyped an independent sample of mothers with a history of an NTD-affected pregnancy derived from the same Irish population. In this sample there was a significant excess of 1958AA homozygote mothers of NTD cases (n=245) compared to controls (n=770). The direction and magnitude of risk (odds ratio 1.49 (1.07-2.09), P=1;0.019) is consistent with our earlier finding. Sequencing of the MTHFD1 gene revealed that this association is not being driven by another common variant within the coding region. We have established that the MTHFD1 1958>A polymorphism has a significant role in influencing a mother's risk of having an NTD-affected pregnancy in the Irish population.

Original languageEnglish (US)
Pages (from-to)768-772
Number of pages5
JournalEuropean Journal of Human Genetics
Volume14
Issue number6
DOIs
StatePublished - Jun 2006

Keywords

  • C1 synthase
  • Folate
  • Irish
  • MTHFD1
  • NTD
  • Spina bifida

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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