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

doi:10.1016/j.ajog.2017.05.023

American Journal of Obstetrics and Gynecology

Volume 217, Issue 3, September 2017, Pages 367.e1-367.e9

Presented as an oral abstract at the 37th annual meeting of the Society for Maternal-Fetal Medicine, Las Vegas, NV, Jan. 23–28, 2017.

https://doi.org/10.1016/j.ajog.2017.05.023 Get rights and content

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 whether genetic variation in the oxytocin receptor (OXTR) or in the gene encoding G protein–coupled receptor kinase 6 (GRK6), which regulates desensitization of the oxytocin receptor, 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 single-nucleotide polymorphisms in OXTR and 7 haplotype-tagging single-nucleotide polymorphisms 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 the 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 used. Race/ethnicity was included in all models because of 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. Eighteen haplotype-tagging single-nucleotide polymorphisms within OXTR and 7 haplotype-tagging single-nucleotide polymorphisms within GRK6 were examined. Five single-nucleotide polymorphisms in OXTR showed nominal significance with maximal infusion rate of oxytocin, and two single-nucleotide polymorphisms in OXTR were associated with total oxytocin dose received. One single-nucleotide polymorphism in OXTR and two single-nucleotide polymorphisms in GRK6 were associated with duration of labor, one of which met the multiple testing threshold (P = .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 single-nucleotide polymorphisms, two in OXTR and one in GRK6, showed nominal significance with mode of delivery.

Conclusion

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.

Section snippets

Materials and Methods

To determine whether OXTR and GRK6 genotype is associated with oxytocin dosing and labor outcomes among women at term, we genotyped women participating in the Healthy Pregnancy, Healthy Baby study at Duke University Medical Center.14, 15 The Healthy Pregnancy, Healthy Baby cohort study is a key component of the Southern Center on Environmentally Driven Disparities in Birth Outcomes, an interdisciplinary center with the goal of understanding how environmental, social, and host factors contribute

Results

DNA was available from 482 women from the non-Hispanic white, non-Hispanic black, Hispanic, and non-Hispanic Asian groups for analysis. The racial and ethnic breakdown of the included subjects is listed in Table 1. The mean age of the population was 26.9 years (SD, 6.4) and the mean prepregnancy BMI was 30.1 kg/m² (SD, 9.4).

The most common indications for induction were postdates (n = 116, 24.1%), gestational hypertension or preeclampsia (n = 90, 18.7%), chronic hypertension (n = 66, 13.7%),

Comment

In this study, we demonstrate that maternal genotype in the OXTR and GRK6 genes are associated with oxytocin dosing and labor outcomes among women undergoing induction of labor near term. These findings are significant because they demonstrate that variation in maternal genes is important in oxytocin receptor function and that desensitization may influence the amount of oxytocin required for induction, the duration of labor, and overall cesarean delivery rates. With further research, this work

Acknowledgments

We thank the entire Children’s Environmental Health Initiative group at Rice University, the University of Michigan, and Duke University for providing access to the Health Pregnancy, Health Baby DNA samples and study data. We also thank Simon Gregory and Steve Siecinski, both of Duke University, for providing ideas and assistance with displaying our data on the OXTR and GRK6 gene maps in Figure 3. Finally, we thank Simon Gregory and Karen Abramson of the Duke Molecular Physiology Institute’s

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: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development award K08HD070872 (to C.A.G.) as well as by the Josiah Charles Trent Memorial Foundation Endowment Fund of Duke University (to C.A.G.). In addition, this research was supported by support from the National Institutes of Health (grant 5P2O-RR020782-O3) and the US Environmental Protection Agency (grant RD-83329301-0).

: The authors report no conflict of interest.

: Cite this article as: Grotegut CA, Ngan E, Garrett ME, et al. 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. Am J Obstet Gynecol 2017;217:367.e1-9.

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Meeting PaperSMFM PaperThe 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

Background

Objective

Study Design

Results

Conclusion

Section snippets

Materials and Methods

Results

Comment

Acknowledgments

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

J Biol Chem

Am J Hum Genet

Am J Obstet Gynecol

J Biol Chem

Oxytocin pharmacodynamics: effect of long infusions on uterine activity

Gynecol Obstet Invest

Oxytocin during labour and risk of severe postpartum haemorrhage: a population-based, cohort-nested case-control study

BMJ Open

Loss of myometrial oxytocin receptors during oxytocin-induced and oxytocin-augmented labour

J Reprod Fertil

Meeting Paper
SMFM Paper
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