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
| Autor: | Peadar N. Kirke, John M. Scott, Alexander S. Whitehead, Dorothy Ramsbottom, Anne M. Molloy, James L. Mills, Helen Burke, Donald G. Weir, Denis C. Shields |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Folate Genotype Mothers Genetic determinism Genomic Imprinting Gene Frequency Enzyme Stability Odds Ratio Genetics Humans Genetics(clinical) Genetic Predisposition to Disease Neural Tube Defects Allele Risk factor Thermolabile Spina bifida Homocysteine Allele frequency Alleles Methylenetetrahydrofolate Reductase (NADPH2) Genetics (clinical) Family Health Oxidoreductases Acting on CH-NH Group Donors biology Methylenetetrahydrofolate reductase Thermolabile variant Temperature Genetic Variation Odds ratio Embryo Mammalian Linear Models biology.protein Female Ireland Research Article |
| Zdroj: | The American Journal of Human Genetics. 64:1045-1055 |
| ISSN: | 0002-9297 |
| Popis: | SummaryRecent 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. |
| Databáze: | OpenAIRE |
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