Alcohol dehydrogenase SNPs and risk of human oral clefting: different effects of maternal and child genotypes

Background & Aim: About 70% of human cases of oral clefting are isolated and
nonsyndromic. Non syndromic cleft lip and palate (CL/P) has high heritability, but
multiple susceptibility genes and environmental interactions underlie its etiology.
Since this birth defect occurs during the first trimester of pregnancy, both the
mother’s and the child’s genotypes may affect disease risk, further complicating
analyses of candidate gene SNP associations. Advances in molecular technologies
have made it possible to the genotype high probability gene SNPs that may be directly
involved in oral clefting.
Method and materials: We conducted a family-based association study of SNPs in
alcohol dehydrogenase (ADH) genes and maternal alcohol consumption during
pregnancy. We used a newly developed statistical approach, which assesses effects of
the maternal and affected child’s genotypes on disease risk. Our sample included 163
families with ³1 CL/P-affected member and 448 subjects with DNA available for
genotyping. Two SNPs in ADH2 and one in ADH3 were genotyped by PCR-RFLP or
OLA methods.
Results: Associations in opposite direction was found for mothers’ and affected
children’s genotypes for two SNPs. For example, risk was increased in children
having the ADH3 “12” genotype, but decreased in mothers with this same genotype.
We also found a significantly elevated frequency of the slow metabolizing“12” and
“22” genotypes of the ADH3 SNP in CL/P-affected children whose mothers
consumed alcohol during the first trimester compared to affected children whose
mothers didn’t drink. This suggests a gene by environment interaction: CL/P risk
associated with the child’s genotype at this SNP depends on maternal alcohol
exposure.
Conclusion: These examples illustrate some of the issues that must be incorporated
into SNP linkage disequilibrium studies of complex diseases.
Key Words: Birth Defects, Cleft Lip and Cleft Palate, Transmission Disequilibrium
test, Gene by Environment Interactions, ADH2, ADH3