Maternal EPHX1 polymorphisms and risk of phenytoin-induced congenital malformations.

OBJECTIVES: The teratogenic effects of the anti-epileptic drug phenytoin have been linked to genetic differences in phenytoin disposition. The goal of this study was to assess the effect of maternal genotype of functional polymorphisms in two genes involved in phenytoin metabolism, CYP2C9 (R144C, I395L) and EPHX1 (Y113H, H139R), on the presence of major craniofacial abnormalities (CFAs) in the child. METHODS: We used data from the Collaborative Perinatal Project (1959-1974), a study involving 42 000 mothers and 55 000 children to assess the effect of maternal genotype. We studied 174 pregnancies in 155 women who used phenytoin throughout their pregnancy, gave birth to a live child and had available stored blood specimens suitable for DNA extraction. RESULTS: Nineteen children had CFA. In a logistic regression model adjusted for history of phenytoin use during the first trimester and maternal epilepsy (N=157 pregnancies), the maternal EPHX1 113 H [per rare allele odds ratio (OR): 2.43, 95% confidence interval (CI): 1.16-5.10, P=0.02] and 139 R (per rare allele OR: 2.33, 95% CI: 1.09-5.00, P=0.03) alleles were associated with CFAs in the child. The maternal EPHX1 Y113/H139 (common) haplotype showed a significant protective association with CFAs in the child (OR: 0.29, 95% CI: 0.12-0.68, P=0.004), when compared to other haplotypes. CYP2C9 genotype was not related to fetal endpoints. CONCLUSION: Maternal EPHX1 genotype may be associated with risk of fetal anomalies among pregnant women taking phenytoin. Future study is required to confirm these results in larger, independent populations.

Functional profiling of uncommon VCAM1 promoter polymorphisms prevalent in African American populations.

Multiple variants of the vascular adhesion molecule-1 (VCAM1) promoter show increased nucleotide heterozygosity in the African American population. Using a novel transfection-based transcriptional pathway profiling method, we show that select uncommon variants are functionally hyperactive. Eight candidate VCAM1 promoter haplotypes comprising 13 previously identified SNPs were assessed for response to known mitogens. Activity was correlated with bioinformatic analysis of hyper- and hyporesponsive variants to identify the gain or loss of haplotype-specific transcription factor binding site (TFBS). Using this approach, a low frequency regulatory allele (c.-540A>G; dbSNP rs3783605:A>G), found in a hyperactive VCAM1 promoter haplotype, was shown to create a candidate binding site for ETS2 that was confirmed in vivo by chromatin immunoprecipitation. This report provides the first functional evaluation of VCAM1 promoter polymorphisms and establishes a hypothetical foundation for investigation of their role in the pathogenesis of VCAM1-associated diseases that disproportionately afflict African Americans, including thromboembolic diseases, asthma, and multiple myeloma.

Association between chronic disseminated candidiasis in adult acute leukemia and common IL4 promoter haplotypes.

Chronic disseminated candidiasis (CDC) is a form of Candida species infection observed primarily in patients with acute leukemia. To investigate possible genetic factors associated with CDC, we conducted a pilot study of 40 patients with both leukemia and CDC and 50 control patients with leukemia only. A common haplotype of the IL4 promoter (-1098T/-589C/-33C) was overrepresented in patients with CDC (P= .01; odds ratio [OR], 2.16), whereas another common haplotype (-1098T/-589T/-33T) appeared to be protective against CDC (P= .018; OR, 0.47). Genetic variants of IL4 could contribute to the development of CDC in patients with acute leukemia.