The role of mother/infant alcohol dehydrogenase 2, cytochrome P450 2E1 and aldehyde dehydrogenase 2 genotype in the development of fetal alcohol spectrum disorders

Abstract

Fetal Alcohol Syndrome (FAS) and Fetal Alcohol Spectrum Disorders (FASD) are the most common forms of preventable mental retardation affecting children today resulting from prenatal ethanol exposure. It is not currently known if ADH2, Cyp2E1 and/or ALDH2 genotypes or some combination of the three, in mothers and infants, in addition to maternal ethanol intake, increase the likelihood of developing FAS/FASD. A better understanding of the influence of genetic factors on the development of FAS/FASD should allow identification of high risk mothers to target for intervention and improved quality of life for potentially affected infants. To more clearly determine the role of ADH2, Cyp2E1, and ALDH2 in the development of FAS, this research examined the collective effects of polymorphisms in these enzymes. ADH2, Cyp2E1 and ALDH2 genotypes were analyzed in a cohort of 69 mother/infant pairs well characterized with respect to maternal alcohol consumption. The influence of genotype combinations on correlations between maternal ethanol intake and infant outcomes including birth weight, birth length, head circumference Six and twelve month developmental indices were also examined. Mothers possessing the ADH2*3 allele were shown to drink borderline significantly less than mothers lacking the allele (p=0.08). Mothers possessing the Cyp2E1 insertion also showed a borderline significant trend toward lighter drinking (p=0.07). Overall, maternal possession of the ADH2*3 allele after prenatal alcohol exposure was associated with better infant outcomes, as was maternal possession of the Cyp2E1 insertion. A trend emerged in the twelve month MDI/PDI scores where infants born to high-drinking mothers had higher MDI and PDI scores than those born to low-drinking mothers also lacking the insertion (p=0.09 and p=0.11, respectively). There were significant associations between the possession of the ALDH2*2 polymorphism and smaller birth length and head circumference. Analysis did not show any correlation between the ADH2/Cyp2E1 combined genotypes and infant outcome. Overall, this study indicated that polymorphisms in the three major genes responsible for alcohol catabolism can play a role in the development of FAS/FASD after prenatal alcohol exposure. Though this study lacks the statistical power to make strong conclusions, trends towards significance were apparent and indicate a need for future studies.