The association of single nucleotide polymorphisms in the oxytocin receptor and G protein-coupled receptor kinase 6 (GRK6) genes with oxytocin dosing requirements and labor outcomes

Abstract Background Oxytocin is a potent uterotonic agent that is widely used for induction and augmentation of labor. Oxytocin has a narrow therapeutic index and the optimal dosing for any individual woman varies widely. Objective The objective of this study was to determine if genetic variation in the oxytocin receptor (OXTR) or in the gene encoding G protein-coupled receptor kinase 6 (GRK6), which regulates desensitization of the OXTR, could explain variation in oxytocin dosing and labor outcomes among women being induced near term. Study Design Pregnant women with a singleton gestation residing in Durham County, NC were prospectively enrolled as part of the Healthy Pregnancy, Healthy Baby cohort study. Those women undergoing an induction of labor at 36 weeks or greater were genotyped for 18 haplotype tagging (ht) single nucleotide polymorphisms (SNPs) in OXTR and 7 htSNPs in GRK6 using TaqMan assays. Linear regression was used to examine the relationship between maternal genotype and maximal oxytocin infusion rate, total oxytocin dose received, and duration of labor. Logistic regression was used to test for association of maternal genotype with mode of delivery. For each outcome, backward selection techniques were utilized to control for important confounding variables and additive genetic models were employed. Race/ethnicity was included in all models due to differences in allele frequencies across populations and Bonferroni correction for multiple testing was used. Results DNA was available from 482 women undergoing induction of labor at 36 weeks or greater. 18 SNPs within OXTR and 7 SNPs within GRK6 were examined. Five SNPs in OXTR showed nominal significance with maximal infusion rate of oxytocin and two SNPs in OXTR were associated with total oxytocin dose received. One SNP in OXTR and two SNPs in GRK6 were associated with duration of labor, one of which met the multiple testing threshold (p=0.0014, rs2731664 [ GRK6 ], mean duration of labor 17.7 hours vs. 20.2 hours vs. 23.5 hours for AA, AC and CC genotypes, respectively). Three SNPs, two in OXTR and one in GRK6 , showed nominal significance with mode of delivery. Conclusions Genetic variation in OXTR and GRK6 is associated with the amount of oxytocin required, as well as the duration of labor and risk for cesarean delivery among women undergoing induction of labor near term. With further research, pharmacogenomic approaches may potentially be utilized to develop personalized treatment to improv