The impact of drug metabolizing enzyme polymorphisms on outcomes after antenatal corticosteroid use

Abstract

Objective To determine the impact of maternal and fetal single nucleotide polymorphisms (SNPs) in key betamethasone (BMZ) pathways on neonatal outcomes. Study design DNA was obtained from women given BMZ and their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway SNPs. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis using relevant clinical variables and genotypes to model for associations with neonatal respiratory distress syndrome (RDS) was performed. Results 109 women delivering 117 babies were analyzed. Sixty-four babies (49%) developed RDS. Multivariable analysis revealed that RDS was associated with maternal SNPs in CYP3A5 (OR 1.63, 95%CI 1.16–2.30) and the glucocorticoid receptor (OR 0.28, 95%CI0.08–0.95) and fetal SNPs in ADCY9 (OR 0.17, 95%CI 0.03–0.80) and CYP3A7*1E (rs28451617, OR 23.68, 95%CI 1.33–420.6). Conclusion Maternal and fetal genotypes are independently associated with neonatal RDS after treatment with BMZ for preterm labor.

Variability in Expression of CYP3A5 in Human Fetal Liver

“…Corticosteroids are metabolized by the CYP3A family of enzymes, and it is conceivable that higher turnover as a result of the CYP3A7*2/ CYP3A5*1 haplotype could reduce the efficacy of antenatal corticosteroids at preventing neonatal respiratory distress syndrome (RDS). In an investigation of the impact of polymorphisms in drug-metabolizing enzymes on the outcome of RDS after administration of maternal betamethasone, Haas et al (2012) showed that maternal CYP3A5 activity score (calculated from genotype) and fetal CYP3A7*1E genotype were predictors of neonatal RDS. Although statistically significant associations with RDS were not observed for the fetal CYP3A5*1 and CYP3A7*2 alleles individually in this study, the investigators did not consider haplotypes across the CYP3A7/CYP3A5 genes, which may reveal an association.…”

Steroid Pathway Genes and Neonatal Respiratory Distress After Betamethasone Use in Anticipated Preterm Birth

“…These findings complement our prior work in that this study specifically looked at a set of genes known to be enriched in the developing lung and go beyond the glucocorticoid receptor pathways we reported previously. 3,4 SNPs in these genes may affect how BMZ acts at the level of the developing fetal lung. Many of these steroid responsive genes are in transcriptional pathways.…”

“…The acquisition of the cohort and samples has been documented elsewhere. 4 Briefly, women admitted to the hospital with threatened preterm delivery who received BMZ were recruited to the study. Informed consent was obtained for all women enrolled and the governing Institutional Review Board approved the study.…”

“…2 We have previously demonstrated that genetic polymorphisms in key drug metabolism and steroid receptor pathways can account for some of the differences in neonatal respiratory outcomes. 3,4 The pathways of steroid response are complex. While our prior studies demonstrated that single nucleotide polymorphisms (SNPs) in adenylate cyclase 9 (ADCY9) and Importin 13 (IPO13) are associated with respiratory distress syndrome (RDS), 3,4 reports from other complex respiratory diseases such as asthma, have uncovered multiple genes involved in respiratory response to steroids.…”

“…3,4 The pathways of steroid response are complex. While our prior studies demonstrated that single nucleotide polymorphisms (SNPs) in adenylate cyclase 9 (ADCY9) and Importin 13 (IPO13) are associated with respiratory distress syndrome (RDS), 3,4 reports from other complex respiratory diseases such as asthma, have uncovered multiple genes involved in respiratory response to steroids. 5,6 A group of steroid genes have been demonstrated to be up-regulated and important in human fetal lung development.…”