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J Hum Genet. 2006;51(2):98-103. Epub 2005 Nov 29.

Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk.

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  • 1Unità Operativa di Neurochirurgia, Istituto G. Gaslini, Largo G. Gaslini 5, 16148 Genoa, Italy.


Genetic variants of enzymes involved in the folate pathway might be expected to have an impact on neural tube defect (NTD) risk. Given its key role in folate metabolism, the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene could represent an attractive candidate in NTD aetiology. In this study, the impact of the MTHFD1 1958G > A polymorphism on NTD risk in the Italian population was examined both by hospital-based case-control and family-based studies. The MTHFD1 1958G > A polymorphism was genotyped in 142 NTD cases, 125 mothers, 108 fathers and 523 controls. An increased risk was found for the heterozygous 1958G/A (OR = 1.69; P = 0.04) and homozygous 1958A/A (OR = 1.91; P = 0.02) genotypes in the children. Significant association was also found when combined 1958G/A and 1958A/A genotypes of cases were compared with the 1958G/G genotype (OR = 1.76; P = 0.02). The risk of an NTD-affected pregnancy of the mothers was increased 1.67-fold (P = 0.04) only when a dominant effect (1958G/A or 1958A/A vs 1958G/G) of the 1958A allele was analysed. The combined TDT/1-TDT (Z = 2.11; P = 0.03) and FBAT (Z = 2.4; P = 0.01) demonstrated a significant excess of transmission of the 1958A allele to affected individuals. In summary, our results indicate that heterozygosity and homozygosity for the MTHFD1 1958G > A polymorphism are genetic determinants of NTD risk in the cases examined.

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