Novel Genetic Variants in the Oxytocin Receptor Predict Oxytocin Non‐Responsiveness in Pregnant Women

Background Oxytocin is used on 43% of all women in the US to induce or augment labor. The maximum oxytocin dose varies between women from ≤2mU/min to ≥20mU/min. Those requiring ≥20mU/min of oxytocin are defined as “non‐responsive.” The biological cause underlying these individual differences in oxytocin response is unknown, however, maternal genetics is suspected to be a factor. Our laboratory has identified three gene variants (H173R, R150L, and R151C) in the oxytocin receptor ( OXTR ) gene in women who are non‐responsive to oxytocin. Hypothesis We hypothesize that variants H173R, R150L, and R151C of the OXTR gene impair ligand binding and receptor signaling and underlie oxytocin non‐responsiveness seen in certain pregnant women. Methods OXTR variants were created via mutagenesis and transfected into HEK293T cells. The oxytocin binding and signaling abilities of the wild‐type OXTR and OXTR variants were then assessed with an ELISA assay using IP1 accumulation as the readout for OXTR signaling. Results H173R, R150L, and R151C are located in the binding and signaling domains of the OXTR and were predicted by the Sorting Intolerant From Tolerant (SIFT) algorithm to be damaging to protein function. Wild‐type OXTR were functional as measured by ELISA and Ca 2+ imaging. Increasing concentrations of oxytocin led to greater stimulation of the OXTR and greater IP1 accumulation. Conclusion Our studies will provide evidence as to whether oxytocin responsiveness can be predicted. This can help improve clinical methods and treatment of women during labor and delivery. Support or Funding Information Supported by the American Physiological Society (to G.Y.L) NIH 1R21 HD076677 (to S.K.E.) and F31 HD079148 (to E.L.R).Transfected with: Oxytocin concentration IP1 concentration (nM)Wild‐type OXTR 0nM 17.57 30nM 27.42 100nM 29.35 1uM 35.07 Un‐transfected 0nM 8.42 1uM 7.97