Genomic Study in Opioid-Treated Cancer Patients Identifies Variants Associated With Nausea-Vomiting

Abstract

Context: Opioids are the mainstay therapy for patients affected by cancer pain. However, about 10%-20% of patients do not benefit from the received analgesic treatment or experience side effects. Genetic variability might account for the variation in individual responses to opioids, both in terms of efficacy and toxicity.

Objectives: The aim of this genome-wide association study (GWAS) was to identify genetic markers of opioid toxicity, in terms of nausea-vomiting.

Methods: Cancer patients receiving morphine, oxycodone, buprenorphine, and fentanyl were recruited from different European countries. Data about toxicity (nausea-vomiting score, NVS) and other relevant clinical information were collected, as well as genotyping data. Regression analysis between genotypes of 2052 patients and NVS was performed, using appropriate covariates, with REGENIE software.

Results: We found 65 variants associated with NVS (P-value < 1.0×10^-5). Of note, 14 intronic variants on chromosome 2 were in NPAS2 gene, encoding a circadian transcription factor reported to play a role in another opioid side effect, the alteration of sleep. Some of these variants were previously identified as splicing quantitative trait loci of the NPAS2 gene.

Conclusions: This is the first GWAS, performed in more than two thousand individually genotyped patients treated with opioids for cancer pain, that investigated the genetic bases of opioid-induced nausea-vomiting. Although further studies are needed to confirm our findings and to characterize the functional role of the identified variants, our results emphasize the importance of performing large pharmacogenomic studies to identify germline variants associated with opioid response, with the ultimate goal of tailoring cancer pain therapies.

Keywords: GWAS; Pharmacogenomics; cancer pain; fentanyl; morphine; side-effects.