GENOME-WIDE ASSOCIATION STUDY IDENTIFIES CANDIDATE GENETIC POLYMORPHISMS ASSOCIATED WITH POSTOPERATIVE NAUSEA AND/OR VOMITING
Authors: Nishizawa *Daisuke , Morino Ryozo , Inoue Rie , Ohka Seii , Kasai Shinya , Hasegawa Junko , Ebata Yuko , Nakayama Kyoko , Sumikura Hiroyuki , Hayashida Masakazu , Yokota Miyuki , Ikeda Kazutaka 
Published: February 2025

Abstract

Background
General anaesthesia is commonly conducted in surgeries for the treatment of cancer or other diseases. Whereas postoperative nausea and/or vomiting (PONV) is known as the most frequent side effect following anaesthesia, considerable individual differences have been widely observed in incidence of PONV. Although four major factors for PONV— female gender, a history of PONV and/or motion sickness, non-smoking status, and the use of postoperative opioids— were incorporated into a simplified risk score to predict PONV that was developed by Apfel et al. (1999) [1], even patients at low PONV risk according to their assigned Apfel score may experience PONV, suggesting a genetic predisposition [2].

Aims and Objectives
To explore potential candidate genetic variants responsible for the inter-subject differences in the incidence of PONV, we conducted genome-wide association study (GWAS) in patients who underwent general anaesthesia to identify potential genetic variants that may significantly contribute to individual differences in PONV.

Method
The subjects in the association study were a total of 806 patients with written informed consent who underwent general anaesthesia by total intravenous anaesthesia (TIVA) with propofol and/or desflurane at The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR). The study protocol was approved by the Institutional Review Board at each related institute. Total genomic DNA was extracted from peripheral blood samples and genotyping was conducted using whole- genome genotyping arrays with more than 900,000 markers and iScan System (Illumina, San Diego, CA, USA). GWAS was conducted in the entire 806 patient subjects to identify potential candidate single nucleotide polymorphisms (SNPs) associated with frequency of nausea and presence/absence of nausea, vomiting, and both of nausea and vomiting (PONV) in trend/additive, dominant, and recessive genetic models. Genome-wide associations were also investigated only in patients with propofol, which was the most common type of anaesthesia in the subjects.

Results
As a result of GWAS in all patients, several two SNPs, rs2776262 and rs140703637 (exm2274524) SNPs in the LOC100506403 and CNTN5 gene regions were significantly associated with frequency of nausea in additive or recessive and dominant models, respectively (P &lt;7.812 × 10-8). In another GWAS only in patients with propofol, rs7212072 and rs12444143 SNPs in the SHISA6 and RBFOX1 gene regions, respectively, were significantly associated with frequency of nausea in additive model as well as the rs2776262 SNP in additive and recessive models, and rs1752136 and rs45574836 (exm1401859) SNPs in the LOC105370198 and ATP8B3 gene regions, respectively, were significantly associated with vomiting in trend model. Among these SNPs, clinical and SNP data were available only for the rs45574836 SNP in independent subjects who underwent laparoscopic gynecological surgery, and the association was replicated in these subjects.

Discussion and Conclusion
The results indicate that rs2776262, exm2274524, rs7212072, rs12444143, rs1752136, and exm1401859 SNPs could serve as markers that predict PONV [3]. Our findings will provide valuable information for achieving satisfactory prophylactic treatment for PONV.

References
[1]Apfel, C.C., Laara, E., Koivuranta, M., Greim, C.A., Roewer, N. (1999) A simplified risk score for predicting postoperative nausea and vomiting: Conclusions from cross-validations between two centers. Anesthesiology, 91, 693–700.;
[2]Klenke, S., Frey, U.H. (2020) Genetic variability in postoperative nausea and vomiting: A systematic review. Eur. J. Anaesthesiol., 37, 959–968.;
[3]Nishizawa, D., Morino, R., Inoue, R., Ohka, S., Kasai, S., Hasegawa, J., Ebata, Y., Nakayama, K., Sumikura, H., Hayashida, M., Yokota, M., Ikeda, K. (2023) Genome-wide association atudy identifies novel candidate variants associated with postoperative nausea and vomiting. Cancers, 15, 4729.