Up to 72% of spina bifida cystica (SB) is preventable by maternal periconceptual folic acid supplementation. The C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene and some other functional polymorphisms are risk factors for SB in some populations. However, despite extensive study, the genetic risk factors for SB are incompletely understood. Polymorphic alleles that diminish bioavailability of reduced folate in the mother during pregnancy could contribute to SB in her fetus, acting in the mother as teratogenic alleles. We recently discovered a polymorphic 19 bp deletion allele (frequency 0.45) within intron-1 of dihydrofolate reductase (DHFR) that is a good candidate for such a genetic factor. Since there is precedence for intron-1 regulatory elements and the deletion allele removes a potential Sp1 transcription factor binding site, we hypothesized that the deletion allele could be functional and act in SB mothers to increase the risk of SB in her fetus. We found that homozygosity for this deletion allele was significantly more frequent in SB mothers, but not in SB fathers or patients, compared with controls and was associated with a significantly increased odds ratio (OR) (2.035) of being an SB mother compared with other genotypes. Genotype distribution obeyed the constraints of Hardy-Weinberg equilibrium in controls, SB patients and fathers, but not in SB mothers. If confirmed, these findings could lead to improved forms of folate supplementation for pregnancy. About half of dietary folates and all of folic acid supplements must be reduced by DHFR to be available for mother and fetus. Reduced folates could be preferable for supplements during pregnancy to prevent SB.
Copyright 2003 Wiley-Liss, Inc.