P18.021.D A genome-wide association study in European advanced cancer patients treated with opioids identified variants regulating the expression of OPRL1 as possible modulators of pain intensity

Background/Objectives: Cancer pain causes an unbearable suffering and lowered quality of life, thus advanced cancer patients often require analgesic therapy. Opioids of step III of the WHO-defined analgesic ladder are the standard of care for the treatment of cancer pain. However, 20-30% of patients do not receive benefits from therapy or have a low response. Literature suggests that genetics plays a role in predisposing patients to a good or poor response to opioids and, herein, we investigated it by performing a genome-wide association study (GWAS). Methods: We individually genotyped 2,060 European advanced cancer patients treated with morphine, buprenorphine, fentanyl, and oxycodone. We performed a whole-genome regression model (using REGENIE software) between genotypes and the opioid response phenotype, defined as a numerical score measuring pain intensity based on patients’ responses to the Brief Pain Inventory Questionnaire. Results: The GWAS identified five non-coding variants on chromosome 20 at P-value 5.0 × 10-8. For all of them, the minor allele was associated with a lower pain intensity. These variants were intronic of PCMTD2 gene and were 200 kbp downstream of OPRL1, the Opioid Related Nociceptine Receptor 1. Interestingly, four of them acted as expression quantitative trait loci, modulating the expression of OPRL1, according to eQTLGen database. Conclusion: This is the largest GWAS performed in this field, so far. Our promising results strengthen the role of genetics in opioid response. Further functional analyses are needed to validate the results obtained and to understand the biological mechanism underlying the association observed.