Differential effects of antiemetic serotonin receptor antagonist Ondansetron on nausea associated with CHRM3 rs2165870 and TACR1 rs3755468 single-nucleotide polymorphisms

Postoperative nausea and vomiting (PONV) after orthognathic surgery is a serious postoperative complication. The cholinergic receptor muscarinic 3 (CHRM3) rs2165870 and tachykinin receptor 1 (TACR1) rs3755468 single-nucleotide polymorphisms (SNPs) have been reported to be involved in PONV. We evaluated the impact of these SNPs on PONV in a Japanese population who underwent orthognathic surgery under PONV prophylaxis with the 5-hydroxytryptamine (serotonin) receptor 3A receptor antagonist ondansetron. In 121 patients, dexamethasone was administered after intubation, followed by ondansetron before the end of surgery. An 11-point numeric rating scale (NRS) score for PONV (0-2 h or 2-24 h after anesthesia endpoint [a.a.e.]) and the presence or absence of metoclopramide administration (0-2 h or 2-24 h a.a.e.) were evaluated. If patients complained of PONV and had an NRS score ≥ 4, then metoclopramide was administered intravenously for PONV rescue. Patients were genotyped for the CHRM3 rs2165870 and TACR1 rs3755468 SNPs, followed by the statistical analysis of associations between these SNPs and phenotypes. AA carriers of CHRM3 rs2165870 received metoclopramide at a significantly higher rate (P = 2.48 × 10^{- 2}) and had higher NRS scores (P = 3.40 × 10^{- 2}) under a diminished influence of ondansetron than GG and GA carriers. CC carriers of TACR1 rs3755468 had significantly higher NRS scores under the sufficient influence of ondansetron than CT and TT carriers (P = 9.97 × 10^{- 3}). Numeric rating scale scores showed a significant interaction between "time" (the effect of ondansetron) and "genotype" (two-way analysis of variance, P = 4.39 × 10^{- 2}). AA carriers of CHRM3 rs2165870 were significantly associated with "time" (P = 3.26 × 10^{- 2}), and CC carriers of TACR1 rs3755468 were not (P > 0.05). These results suggest that ondansetron significantly affects nausea that is associated with CHRM3, whereas it has a minimal effect on nausea that is associated with TACR1. This indicates that nausea that is associated with CHRM3 is qualitatively different from nausea that is associated with TACR1. Ondansetron mainly exerts its effects outside the blood-brain barrier, which may lead to differential impacts on nausea that is associated with CHRM3 and TACR1. These findings may provide future directions for tailor-made preventive measures against PONV that depend on high-risk genotypes of the CHRM3 rs2165870 and TACR1 rs3755468 SNPs.