Drug treatment for nociceptive musculoskeletal pain (NMP) follows a three-step analgesic ladder proposed by the World Health Organization (WHO), starting from non-steroidal anti-inflammatory drugs (NSAIDs), followed by weak or strong opioids until the pain is under control. However, effective pain treatment is challenged by inter-individual differences, and unsatisfied pain treatment response (PTR) rates ranging from 34 to 79% in those suffering from NMP. To investigate the underlying genetic component of PTR, we performed a genome-wide association study (GWAS) in ~ 23,000 participants with NMP from the UK Biobank. In our primary analysis, we compared NSAID vs. opioid users as a reflection of (non)response to NSAIDs, adjusting for age, sex, BMI, population substructure, and study-specific covariates. One genome-wide significant hit was identified in an intergenic region on chromosome 4, rs549224715 (P = 3.88x10-8), and seven signals pass the suggestively significant threshold (P < 1x10-6). All identified loci were in non-coding regions, but most variants showed potential regulatory functions. SNPs in LD (r2 > 0.6) with the lead SNPs passing the nominal significant threshold (P < 0.05) were mapped to 28 target genes in FUMA. Eight of these 28 genes are involved in processes linked to neuropathic pain and musculoskeletal development. Pathway and network analyses with Ingenuity resulted in the identification of immunity-related processes and a (putative) central role of EGFR. Genetic correlation analysis including 596 traits resulted in the identification of 67 nominally significant (P < 0.05) genetic correlations, and these traits were significantly enriched for chronic pain and socioeconomic status traits (P = 3.35 x 10-12). Additionally, we conducted a subtype GWAS for inflammatory NMP and a secondary GWAS for participants with NMP disease history, but no significant hits or overlap with the primary analysis were observed. Overall, we identified one genome-wide significant association in this first GWAS focusing on pain treatment using the analgesic ladder as phenotype. However, we realize that this study lacked power and should be viewed as a first step to elucidate the genetic background of NMP treatment.
The pharmacological management of musculoskeletal pain starts with NSAIDs, followed by weak or strong opioids until the pain is under control. However, the treatment outcome is usually unsatisfying due to inter-individual differences. To investigate the genetic component of treatment outcome differences, we performed a genome-wide association study (GWAS) in ~ 23 000 participants with musculoskeletal pain from the UK Biobank. NSAID vs. opioid users was compared as a re ection of the treatment outcome of NSAIDs. We identi ed one genome-wide signi cant hit in chromosome 4 (rs549224715, P = 3.88×10 − 8 ). Suggestive signi cant (P < 1×10 − 6) loci were mapped to 28 target genes, including eight genes linked to neuropathic pain processes or musculoskeletal development. Pathway and network analyses identi ed immunity-related processes and a (putative) central role of EGFR. However, this study lacked power and should be viewed as a rst step to elucidate the genetic background of musculoskeletal pain treatment.
IntroductionPostoperative pain remains a challenging medical condition impacting the quality of life of every patient. Although several predictive factors for postoperative pain have been identified, an adequate prediction of postoperative pain in patients at risk has not been achieved yet.The primary objective of this study is to identify specific genetic risk factors for the development of acute and chronic postoperative pain to construct a prediction model facilitating a more personalised postoperative pain management for each individual. The secondary objectives are to build a databank enabling researchers to identify other risk factors for postoperative pain, for instance, demographic and clinical outcome indicators; provide insight into (genetic) factors that predict pharmacological pain relief; investigate the relationship between acute and chronic postoperative pain.Methods and analysisIn this prospective, observational study, patients who undergo elective surgery will be recruited to a sample size of approximately 10 000 patients. Postoperative acute and chronic pain outcomes will be collected through questionnaires at different time points after surgery in the follow-up of 6 months. Potential genetic, demographic and clinical risk factors for prediction model construction will be collected through blood, questionnaires and electronic health records, respectively.Genetic factors associated with acute and/or chronic postoperative pain will be identified using a genome-wide association analysis. Clinical risk factors as stated in the secondary objectives will be assessed by multivariable regression. A clinical easy-to-use prediction model will be created for postoperative pain to allow clinical use for the stratification of patients.Ethics and disseminationThe Institutional Review Board of the Radboud university medical centre approved the study (authorisation number: 2012/117). The results of this study will be made available through peer-reviewed scientific journals and presentations at relevant conferences, which will finally contribute to personalised postoperative pain management.Trial registration numberNCT02383342.
The pharmacological management of musculoskeletal pain starts with NSAIDs, followed by weak or strong opioids until the pain is under control. However, the treatment outcome is usually unsatisfying due to inter-individual differences. To investigate the genetic component of treatment outcome differences, we performed a genome-wide association study (GWAS) in ~ 23 000 participants with musculoskeletal pain from the UK Biobank. NSAID vs. opioid users was compared as a reflection of the treatment outcome of NSAIDs. We identified one genome-wide significant hit in chromosome 4 (rs549224715, P = 3.88×10− 8). Suggestive significant (P < 1×10 − 6) loci were mapped to 28 target genes, including eight genes linked to neuropathic pain processes or musculoskeletal development. Pathway and network analyses identified immunity-related processes and a (putative) central role of EGFR. However, this study lacked power and should be viewed as a first step to elucidate the genetic background of musculoskeletal pain treatment.
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