MTHFR 677C-->T and 1298A-->C polymorphisms: evaluation of maternal genotypic risk and association with level of neural tube defect

Background: Neural tube defects (NTDs) are common birth defects (1 in 1,000) leading to significant morbidity and mortality. Periconceptional folic acid supplementation helps in prevention of 70% of NTDs. Recently, polymorphisms in genes encoding enzymes of the folate pathway have been implicated in causation of NTDs. Since the closure of neural tube occurs at multiple sites, the etiology of defect at different sites may be different - which explains the failure of folic acid supplementation to prevent all NTDs.

Methods: Molecular analysis of methylenetetrahydrofolate reductase polymorphisms was carried out using polymerase chain reaction and restriction enzyme digestion. We studied the association of these polymorphisms in mothers with a previous child with NTD and further refined the risk by stratification based on level of defect.

Results: The frequency of 677C-->T homozygotes was higher in mothers with a previous child with NTD than the controls (OR = 1.6 (0.38-6.7), 95% CI, p = 0.72) but the difference was statistically insignificant. There was a significant difference in frequency of T alleles among mothers with a previous child with a 'lower' type of defect compared to controls (OR = 2.15 (1.13-4.1), 95% CI, p = 0.02). We did not find any significant association of 1298A-->C polymorphism with the level of NTDs.

Conclusions: We conclude that in the North Indian population, the 677C-->T allele of the MTHFR gene may be associated with the occurrence of a lower type of NTD. This points towards the differential role of thermolabile MTHFR at different sites of neural tube closure.