TMEM132C RS7296262 SINGLE NUCLEOTIDE POLYMORPHISM SHOWED SIGNIFICANT ASSOCIATIONS WITH NAUSEA INDUCED BY OPIOIDS ADMINISTERED FOR CANCER PAIN OR POST-OPERATIVE PAIN
Authors: Kang *Yuna , Ohka Seii , Nishizawa Daisuke , Hasegawa Junko , Nakayama Kyoko , Ebata Yuko , Terui Takeshi , Ishitani Kunihiko , Morino Ryozo , Yokota Miyuki , Koshika Kyotaro , Ichinohe Tatsuya , Ikeda Kazutaka 
Published: February 2025

Abstract

Background
Opioids are almost mandatorily used as analgesia for cancer pain and postoperative pain. Opioid analgesics frequently induce a side effect of nausea which is one of the most unpleasant symptoms. However, the incidence of nausea caused by opioids varies among individuals, and the genomic factors involved are still mostly unknown.

Aims & Objectives
We aim to clarify the genetic background for individual differences in the occurrence of nausea during opioid administration.

Methods
Incidence of nausea was investigated in 428 patients (HS) who received morphine for cancer pain treatment at Higashi-Sapporo Hospital and 806 patients (CIH) who underwent standby surgery under general anesthesia at Cancer Institute Hospital. Genomic DNA was purified from patients’ blood and whole genome genotyping was performed. Nine single nucleotide polymorphisms (SNPs) out of the top 20 SNPs strongly associated with nausea in genome-wide association analysis (GWA) of HS were found in the whole-genome genotyping data of CIH (Nishizawa et al., 2023). Out of these 9 SNPs, only TMEM132C rs7296262 SNP had been reported to be associated with suicide attempts in bipolar disorder subjects in a previous study (Willour et al., 2012). Thus, TMEM132C rs7296262 SNP was further analyzed for the association with nausea in HS and CIH by using SPSS software.

Results
TMEM132C rs7296262 SNP showed a significant association with nausea in HS and CIH (TT+TC vs CC, HS, p = 0.0001; CIH, p = 0.006). In HS, a higher incidence rate of nausea was observed in CC carriers compared to TT+TC carriers (TT+TC/CC (%) are shown: with nausea, 77/23; without nausea, 92/8), while in CIH, a higher incidence rate of nausea was observed in T-allele carriers (with nausea, 87/13; without nausea, 83/17).

Discussion and Conclusion
TMEM132C rs7296262 SNP was significantly associated with nausea during opioid use. The nausea-prone genotype of the rs7296262 SNP was reversed in HS and CIH. Opioids are used chronically for cancer pain, whereas opioids are used acutely during postoperative analgesia. The effect of TMEM132C rs7296262 SNP on nausea may be reversed between the chronic and acute phases of opioid use. The acute administration of morphine may cause an increase in central nervous system expression of substance P and upregulates functional expression of the NK-1 receptor in cortical neurons, while chronic opioid use may lead to long-term repeated activation of mu opioid receptors, resulting in opioid-induced bowel dysfunction that may be associated with nausea and/or vomiting (Howard et al., 2012). Thus, different effects of acute and chronic opioid use may relate to our reversed results on nausea after opioid use.

References
Howard S.S., et al. (2012) Opioid-induced nausea and vomiting. Ann Palliat Med. 1(2):121-129.
Nishizawa D., et al, (2023) Genome-wide association study identifies novel candidate variants associated with postoperative nausea and vomiting. Cancers. 15(19), 4729.
Willour V.L., et al. (2012) A genome wide association study of attempted suicide. Mol Psychiatry. 17(4): 433-444.