Evidence that the risk of spina bifida is influenced by genetic variation at the NOS3 locus

BACKGROUND: There is substantial evidence that the risk of spina bifida, a malformation of the caudal neural tube, may be associated with maternal or embryonic disturbances in the folate-homocysteine metabolic axis. Hence, variants of genes that influence this pathway represent an intriguing group of candidate genes for spina bifida and other neural tube defects (NTD). A common variant of the gene for endothelial nitric oxide synthase (NOS3 G894T) was recently added to this group of NTD candidate genes, based on a report demonstrating that homozygosity for the T allele of this variant is associated with increased homocysteine levels in normal adult populations. METHODS: The association between the risk of spina bifida and both the maternal and embryonic genotype for the NOS3 G894T variant was evaluated in data from 301 families by using the transmission disequilibrium test (TDT) and log-linear modeling. RESULTS: Analyses of these data using the TDT provided no evidence that the risk of spina bifida was significantly related to either the maternal or embryonic NOS3 genotype. However, the log-linear analyses indicated that the risk of spina bifida was significantly associated with the embryonic, but not the maternal, genotype for the NOS3 G894T variant. CONCLUSIONS: The results of the present analyses suggest that the embryonic NOS3 G894T genotype is associated with the risk of spina bifida. Moreover, these analyses highlight the importance of a detailed examination of the study data. Had these analyses been restricted to the methodologically simpler TDT, the association between the NOS3 G894T genotype and risk of spina. bifida may well have been overlooked. (C) 2004 Wiley-Liss, Inc.