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Vol. 283, Issue 3, 1095-1101, 1997
Departments of
Pediatrics (D.G.M.),
Pharmacology (D.G.M.), and
Obstetrics and Gynecology (S.S.M., R.J.S.), Wayne State University
School of Medicine, Detroit, Michigan, and
Department of Internal
Medicine, Indiana University School of Medicine, Indianapolis, Indiana
(H.R.T., T.-K.L.)
Considerable variation in offspring outcome is observed after
intrauterine alcohol exposure. The underlying mechanism may include
genetic diversity in the enzymes responsible for alcohol metabolism. Of
the known genetic polymorphisms, differences at the alcohol
dehydrogenase-2 locus (ADH2) are likely most critical because the resulting enzymes are >30-fold different in their kinetic
constants. To test whether differences in maternal or offspring
ADH2 genotype are determinants of risk for 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 Scales of Infant Development Mental Index (MDI) at 12 months
of age. Drinking during pregnancy was associated with lower MDI scores but only in the offspring of mothers without an ADH2*3
allele (P < .01, analysis of variance, post
hoc). The offspring of drinking women with at least one
ADH2*3 allele had MDI scores similar to those of nondrinking
women of either ADH2 genotype. Lower MDI scores were
associated with the three-way interaction among increasing alcohol
intake and maternal and offspring absence of the ADH2*3 allele (P < .01, multiple linear regression). We suggest that the
protection afforded by this allele is secondary to its encoding of the
high-Km/high-Vmax ADH
3 isoenzyme, which would provide more efficient alcohol metabolism
at high blood alcohol concentrations. These observations are supportive
of alcohol, rather than acetaldehyde, being the more important
proximate teratogen and are the first observations of a specific
genetic explanation for susceptibility differences to alcohol-related
birth defects.
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