Analysis of the EPHX1 113 polymorphism and GSTM1 homozygous null polymorphism and oral clefting associated with...

Maternal cigarette smoking during the first trimester of pregnancy is associated with an increased risk of having a child with an oral cleft. Compounds present in cigarette smoke undergo bioactivation and/or detoxication. Phase I of this process results in the formation of reactive epoxides, which can form DNA adducts initiating and promoting mutagenesis, carcinogenesis, or teratogenesis. Microsomal epoxide hydrolase (mEH; gene symbol EPHX1) catalyzes hydrolysis of epoxides. Phase II involves attachment of a moiety (e.g., glutathione) to the compound mediated by a variety of enzymes, including glutathione S-transferase, generally resulting in a decreased reactivity. Recent studies suggest an association between the EPHX1 codon 113 polymorphism or homozygous null GSTM1 allele and the risk of carcinogenesis, emphysema, phenytoin-associated oral clefting, and the risk of spontaneous abortion. This study explores the association between EPHX1 codon 113 and homozygous null GSTM1 genotypes and oral clefting among infants whose mothers smoked during pregnancy. Case infants were diagnosed with isolated cleft lip with or without cleft palate (CL/P). EPHX1 codon 113 allelotyping was performed on 195 samples (85 cases, 110 controls) by PCR/RFLP analysis. 130 samples (79 cases, 51 controls) were tested for the GSTM1 homozygous null genotype using PCR. Using the odds ratio as a measure of association, we did not observe elevated risks of CL/P associated with either allelic comparison. This suggests that when mothers smoke periconceptionally, their infants having these alleles at either (or both) loci were not at substantially increased risk for CL/P compared to infants with the wild-type alleles.