Faculty Collaboration Database

Alcohol dehydrogenase-2*3 allele protects against alcohol-related birth defects among African Americans. J Pharmacol Exp Ther 1997 Dec;283(3):1095-101

Date

02/12/1998

Pubmed ID

9399981

Scopus ID

2-s2.0-0031456078 (requires institutional sign-in at Scopus site)   134 Citations

Abstract

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 beta3 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.

Author List

McCarver DG, Thomasson HR, Martier SS, Sokol RJ, Li T

MESH terms used to index this publication - Major topics in bold

Abnormalities, Drug-Induced
Adolescent
Adult
Alcohol Dehydrogenase
Alleles
Female
Genotype
Growth
Humans
Infant, Newborn
Isoenzymes
Male
Pregnancy