A European pharmacogenomic study of the response to opioids in advanced cancer patients identifies germline variants associated with nausea-vomiting side effect

Abstract Opioids are the mainstay therapy for patients affected by moderate to severe cancer pain, yet in about 10–20% of the cases, 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. The aim of this genome-wide association study (GWAS) was to identify new genetic markers of opioid toxicity in terms of nausea-vomiting. Cancer patients receiving morphine, oxycodone, buprenorphine, and fentanyl were recruited from different European cancer centers. Data about toxicity (nausea-vomiting score, NVS) and other relevant clinical information were collected. DNA samples were genotyped using Axiom Precision Medicine Research Arrays. Linear regression between genotypes of 2,059 patients and NVS was performed, using the REGENIE pipeline. Sex, age, study, and country were included in the model as covariates. We found 68 variants associated with NVS (P-value < 1.0 x 10− 6). Of note, 15 intronic variants on chromosome 2 were located in the 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. 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 goals of improving personalization of cancer pain therapies.