vidual but high attributable risk in the population. In cases of high heritability, the disease trait might have alleles of several major genes and of several modifier genes contributing to its penetrance and expressivity. In those with low heritability, there might be alleles of several genes as well as specific environmental factors that together increase the risk of disease in a population.

Recent examples in which gene-environment interactions have been sucessfully elucidated for developmental defects are the following:

  • Transforming growth factor (TGFα) polymorphisms and oral clefts: Evidence for an association between maternal smoking and oral clefts has been equivocal (Hwang et al. 1995). In this study, there was not an overall significant association between maternal smoking and oral clefts in the newborn. However, if the newborn had a variant allele (TAQL C2) of the TGFα gene, the odds ratio for oral clefts in infants of smoking mothers (more than 10 cigarettes per day) was 8.7, a 10-fold increase compared with infants of smoking mothers who did not have this variant allele. The variant allele alone was not associated with increased risk for oral clefts. TGFα is a ligand of a tyrosine kinase receptor.

  • Homeobox gene MSX1, limb deficiencies, and smoking: Frequencies of rare alleles at the MSX1 locus are slightly higher in infants with limb deficiencies compared with infants having other types of developmental defects (odds ratio 2.4). Infants carrying the rare alleles had a 2-fold increased risk of a limb deficiency when the mother smoked during pregnancy (odds ratio 4.8) compared with infants harboring the rare allele whose mothers did not smoke. Smoking alone was not associated with increased risk for limb deficiencies in this study (Hwang et al. 1998). MSX1 is a transcription factor whose activity often depends on BMP2,4 signals.

  • Variable human susceptibility to developmental defects due to diphenylhydantoin (DPH or phenytoin): 10-20% of the offspring of epileptic women taking phenytoin during pregnancy have the fetal hydantoin syndrome (Hanson et al. 1976; van Dyke et al. 1988). Phenytoin is thought to be converted to a reactive intermediate to have teratogenic effects (Martz et al. 1977; for a review, see Finnell et al. 1997a). The population variability in response to phenytoin possibly reflects a heterogeneity of DME genotypes. In a pair of twin births in which only one twin had dysmorphologies of the hydantoin syndrome, the mother and the affected twin had decreased activity of the enzyme epoxide hydroxylase compared with the unaffected twin (Buehler 1984). Buehler et al. (1990) subsequently showed that children with the hydantoin syndrome indeed have lower activity of epoxide hydrolase. Epoxide hydrolase would serve to detoxify an arene oxide intermediate of phenytoin, and it has been suggested that reduced activity of this enzyme is responsible for increased susceptibility to phenytoin. Hassett et al. (1994) reported a polymorphism in the epoxide hydrolase gene that markedly decreases enzyme activity. Conversely, the DPH parent compound might be teratogenic, and genetic defects in CYP2C9 and CYP2C19 (the two



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