title: A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group.
abstract: Women who take folic acid periconceptionally reduce their risk of having a child with a neural tube defect (NTD) by >50%. A variant form of methylenetetrahydrofolate reductase (MTHFR) (677C-->T) is a known risk factor for NTDs, but the prevalence of the risk genotype explains only a small portion of the protective effect of folic acid. This has prompted the search for additional NTD-associated variants in folate-metabolism enzymes. We have analyzed five potential single-nucleotide polymorphisms (SNPs) in the cytoplasmic, nicotinamide adenine dinucleotide phosphate-dependent, trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1) for an association with NTDs in the Irish population. One SNP, R653Q, in this gene appears to be associated with NTD risk. We observed an excess of the MTHFD1 "Q" allele in the mothers of children with NTD, compared with control individuals. This excess was driven by the overrepresentation of QQ homozygotes in the mothers of children with NTD compared with control individuals (odds ratio 1.52 [95% confidence interval 1.16-1.99], P=.003). We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD, USA.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.forename: Mary
authors.initials: M
authors.lastname: Conley
authors.forename: Christopher
authors.initials: C
authors.lastname: Cox
authors.forename: Peadar N
authors.initials: PN
authors.lastname: Kirke
authors.forename: Mary P
authors.initials: MP
authors.lastname: McKeever
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Leary
authors.forename: Anne
authors.initials: A
authors.lastname: Parle-McDermott
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Swanson
mesh_terms: D000619:Aminohydrolases / Q000235:genetics*; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics*; D006801:Humans; D007494:Ireland; D045064:Methenyltetrahydrofolate Cyclohydrolase; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D045064:Methenyltetrahydrofolate Cyclohydrolase; D005574:Formate-Tetrahydrofolate Ligase