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 improve safety and efficacy outcomes among women undergoing induction of labor.

Poor Uterine Contractility as Maternal Predisposition to Postpartum Hemorrhage Among Low-Risk Women: An Analysis of Large-Scale Database

“…Some pathogenic dysfunction may also play a role, including such as the synthesis dysfunction of oxytocin and prostaglandins or decreased sensitivity or expression of OXTRs, FP receptors, EP1 receptors, or EP3 receptors. Reinl et al [28] have suggested that some OXTR gene variants are associated with increased oxytocin responsiveness during labor. Grotegut et al [29] reported that the genetic variation in OXTR and gene encoding G protein-coupled receptor kinase-6, which regulates desensitization of the OXTR, is associated with the amount of oxytocin required as well as the duration of labor.…”

Influence of oxytocin receptor single nucleotide sequence variants on contractility of human myometrium: an in vitro functional study

“…A previous study showed an association between this sequence variant and a lower risk for cesarean section among women induced near term. This lower cesarean section rate was associated with a lower OXT dose, lower maximal OXT infusion rate and lower duration of labor induction with OXT [11]. Increased response of the myometrium to OXT stimulation might explain the observed lower cesarean rate.…”

“…Our work, performed with myometrium samples from 60 patients, suggests that patients with rs237888 and/or rs4686302 may be more sensitive to OXT stimulation. This might explain why patients with these variants less often need a cesarean in the course of labor induction with OXT [11] and were thought to be prone to preterm labor [8], respectively]. Additional research should estimate possible clinical benefits of introducing an rs237888 and rs4686302 screening at pregnancy begin.…”

“…Other studies revealed that a combination of three common minor allelic variants from the OXTR can increase preterm birth risk [9], and that the minor allele of the common rs53576 variant is associated with a long transition to active labor [10]. Finally, there are some indications that OXTR single-nucleotide variants may affect the response to OXT-treatment with regard to labor induction and augmentation, mode of delivery and prevalence of preterm birth [11].…”

Oxytocin Receptor Signaling in Vascular Function and Stroke

“…Oxytocin receptor is considered a Class A GPCR with respect to its interaction with β-arrestins, meaning that it maintains a strong connection with β-arrestin to regulate its endocytosis into secretory or degradative pathways ( Conti et al, 2009 ). The interaction of OXTR with β-arrestins, and therefore its desensitization, is initiated by phosphorylation of the receptor by G protein receptor kinase 6 ( Grotegut et al, 2016 , 2017 ). Studies on OXTR tagged with GFP suggest that many receptors are recycled back though the secretory pathway, indicating a more sustained need for OXTR pathway signaling.…”