ALCOHOL DEHYDROGENASE-2-ASTERISK-3 ALLELE PROTECTS AGAINST ALCOHOL-RELATED BIRTH-DEFECTS AMONG AFRICAN-AMERICANS

Considerable variation in offspring outcome is observed after intraute rine alcohol exposure. The underlying mechanism may include genetic di versity in the enzymes responsible for alcohol metabolism, Of the know n genetic polymorphisms, differences at the alcohol dehydrogenase-2 lo cus (ADH2) are likely most critical because the resulting enzymes are >30-fold different in their kinetic constants. To test whether differe nces in maternal or offspring ADH2 genotype are determinants of risk f or alcohol-related birth defects, maternal-infant pairs (n =243) were enrolled on the basis of maternal alcohol intake during pregnancy and maternal ADH2 genotype. Infant outcome was measured using the Bayley S cales of Infant Development Mental Index (MDI) at 12 months of age. Dr inking during pregnancy was associated with lower MDI scores but only in the offspring of mothers without an ADH23 allele (P <.01, analysis of variance, post hoc). The offspring of drinking women with at least one ADH23 allele had MDI scores similar to those of nondrinking wome n of either ADH2 genotype, Lower MDI scores were associated with the t hree-way interaction among increasing alcohol intake and maternal and offspring absence of the ADH23 allele (P <.01, multiple linear regres sion). We suggest that the protection afforded by this allele is secon dary to its encoding of the high-K-m/high-V-max ADH beta 3 isoenzyme, which would provide more efficient alcohol metabolism at high blood al cohol concentrations. These observations are supportive of alcohol, ra ther than acetaldehyde, being the more important proximate teratogen a nd are the first observations of a specific genetic explanation for su sceptibility differences to alcohol-related birth defects.