Interaction of folate and homocysteine pathway genotypes evaluated in susceptibility to neural tube defects (NTD) in a German population

Neural tube defects (NTD) are likely to result from an interaction of sever al genes and environmental factors. Because periconceptional folate intake reduces the NTD risk in the fetus, and because mothers of children with NTD showed elevated plasma homocysteine levels, gene polymorphisms of the fola te and homocysteine pathway, such as 5,10-methylenetetrahydrofolate reducta se (MTHFR) 677C -->T, MTHFR 1298A -->C and cystathionine beta -synthase (CB S) 844ins68, have been implicated in the etiology of NTD. Several studies h ave demonstrated that these polymorphisms may indeed be associated with NTD in some populations. In order to evaluate the role of these polymorphisms and their interaction in NTD, we genotyped 417 individuals for case-control studies and 129 families for transmission disequilibrium tests. We are the first to present detailed data on MTHFR haploid genotypes in combination w ith CBS 844ins68. The MTHFR risk genotype 677CT/1298AC, known to be associa ted with decreased enzyme activity and increased homocysteine, was found si gnificantly more often in patients than in controls (P = 0.02). A CBS inser tion allele in addition to MTHFR 677CT/1298AC heterozygosity or MTHFR 677TT /1298AA homozygosity did not result in an increased risk for NTD. This is i n agreement with the recently reported homocysteine-lowering effect of the CBS 844ins68 allele in carriers of MTHFR variants.