title: The "thermolabile" variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of genetic risk and the relative importance of the genotypes of the embryo and the mother.
abstract: Recent reports have implicated the "thermolabile" (T) variant of methylenetetrahydrofolate reductase (MTHFR) in the causation of folate-dependent neural tube defects (NTDs). We report herein the largest genetic study of NTD cases (n=271) and families (n=218) to date, establishing that, in Ireland, the "TT" genotype is found in 18.8% of cases versus 8.3% of controls (odds ratio 2.57; confidence interval [CI] 1.48-4.45; P=.0005). The maternal and paternal TT genotypes have intermediate frequencies of 13.8% and 11.9%, respectively, indicating that the predominant MTHFR-related genetic effect acts via the TT genotype of the developing embryo. Analysis of the 218 family triads of mother, father, and affected child with log-linear models supports this interpretation, providing significant evidence that the case TT genotype is associated with NTDs (P=.02) but no evidence of a maternal TT genotypic effect (P=. 83). The log-linear model predicted that the risk of NTDs conferred by the case TT genotype is 1.61 (CI 1.06-2.46), consistent with the paramount importance of the case TT genotype in determining risk. There is no compelling evidence for more than a modest additional risk conferred by a maternal TT genotype. These results favor a biological model of MTHFR-related NTD pathogenesis in which suboptimal maternal folate status imposes biochemical stress on the developing embryo, a stress it is ill-equipped to tolerate if it has a TT genotype.
authors: Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Trinity College, Dublin, Ireland.
authors: D C
authors: DC
authors: Shields
authors: P N
authors: PN
authors: Kirke
authors: J L
authors: JL
authors: Mills
authors: D
authors: D
authors: Ramsbottom
authors: A M
authors: AM
authors: Molloy
authors: H
authors: H
authors: Burke
authors: D G
authors: DG
authors: Weir
authors: J M
authors: JM
authors: Scott
authors: A S
authors: AS
authors: Whitehead
mesh_terms: D000483:Alleles; D004622:Embryo, Mammalian / Q000201:enzymology / Q000378:metabolism*; D004795:Enzyme Stability; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D007494:Ireland; D016014:Linear Models; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009035:Mothers; D009436:Neural Tube Defects / Q000201:enzymology / Q000235:genetics*; D016017:Odds Ratio; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism; D013696:Temperature
chemical_list: D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)