EXPLORING GENE-GENE INTERACTIONS IN THE ETIOLOGY OF NEURAL-TUBE DEFECTS

The role of susceptibility genes in the etiology of birth defects is u nclear, but may involve in some cases multiple alleles at multiple loc i. We suggest a simple epidemiologic approach to explore gene-gene int eractions, and use it to reevaluate data from a recent case-control st udy on the possible association of neural tube defects (NTDs) with spe cific mutations of two genes, 5,10-methylene-tetrahydrofolate reductas e (MTHFR) and cystathionine-beta synthase (CBS). We found that, compar ed with the common genotype, homozygosity for the MTHFR mutation alone was associated with a two-fold increased risk for NTDs, while homozyg osity for the CBS mutation alone was not a risk factor. However, homoz ygous individuals for the mutations at both loci had a five-fold great er risk for NTDs than those with the reference genotype. Though the or iginal study was too small to detect statistically significant differe nces among most of the risk estimates, these results, if confirmed by independent and larger studies, suggest that gene-gene interaction may play a role in modulating the susceptibility to NTDs in a proportion of affected individuals. This approach, moreover, could be a valuable adjunct to the study of gene-gene interactions in the etiology of huma n disease.