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OtherDEVELOPMENTAL PHARMACOLOGY

Alcohol Dehydrogenase-2*3 Allele Protects Against Alcohol-Related Birth Defects Among African Americans

D. G. McCarver, H. R. Thomasson, S. S. Martier, R. J. Sokol and T.-K. Li
Journal of Pharmacology and Experimental Therapeutics December 1997, 283 (3) 1095-1101;
D. G. McCarver
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H. R. Thomasson
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S. S. Martier
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R. J. Sokol
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T.-K. Li
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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 offspringADH2 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*3allele (P < .01, analysis of variance, post hoc). The offspring of drinking women with at least oneADH2*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*3allele (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 β3 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.

Footnotes

  • Send reprint requests to: D. Gail McCarver, M.D., Associate Professor of Pediatrics and Pharmacology, Wayne State University, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201. E-mail: dgmccar{at}med.wayne.edu.

  • ↵1 This work was supported by a grant from the March of Dimes and United States Public Health Service Grants AA07606 and AA07611.

  • ↵2 Current address: Lilly Laboratories, Wishard Memorial Hospital, 1001 West 10th Street, Indianapolis, IN 46202.

  • Abbreviations:
    ADH
    alcohol dehydrogenase
    ALDH
    aldehyde dehydrogenase
    CYP2E1
    cytochrome P4502E1
    MDI
    Mental Developmental Index
    ANOVA
    analysis of variance
    • Received April 25, 1997.
    • Accepted August 26, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 3
1 Dec 1997
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OtherDEVELOPMENTAL PHARMACOLOGY

Alcohol Dehydrogenase-2*3 Allele Protects Against Alcohol-Related Birth Defects Among African Americans

D. G. McCarver, H. R. Thomasson, S. S. Martier, R. J. Sokol and T.-K. Li
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1095-1101;

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Alcohol Dehydrogenase-2*3 Allele Protects Against Alcohol-Related Birth Defects Among African Americans

D. G. McCarver, H. R. Thomasson, S. S. Martier, R. J. Sokol and T.-K. Li
Journal of Pharmacology and Experimental Therapeutics December 1, 1997, 283 (3) 1095-1101;
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