title: Genome-wide association scan of neuropathic pain symptoms post total joint replacement highlights a variant in the protein-kinase C gene.
abstract: Neuropathic pain-like joint symptoms (NP) are seen in a proportion of individuals diagnosed with osteoarthritis (OA) and post total joint replacement (TJR). In this study, we performed a genome-wide association study (GWAS) using NP as defined by the painDETECT questionnaire (score >12 indicating possible NP) in 613 post-TJR participants recruited from Nottinghamshire (UK). The prevalence of possible NP was 17.8%. The top four hits from the GWAS and two other biologically relevant single-nucleotide polymorphisms (SNPs) were replicated in individuals with OA and post TJR from an independent study in the same area (N=908) and in individuals from the Rotterdam Study (N=212). Three of these SNPs showed effect sizes in the same direction as in the GWAS results in both replication cohorts. The strongest association upon meta-analysis of a recessive model was for the variant allele in rs887797 mapping to the protein kinase C alpha (PRKCA) gene odds ratio (OR)possNP=2.41 (95% CI 1.74-3.34, P=1.29 × 10-7). This SNP has been found to be associated with multiple sclerosis and encodes a functional variant affecting splicing and expression of the PRKCA gene. The PRKCA gene has been associated with long-term potentiation, synaptic plasticity, chronic pain and memory in the literature, making this a biologically relevant finding.
authors.affiliation: Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
authors.forename: Sophie C
authors.initials: SC
authors.lastname: Warner
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Joyce Bj
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: Department of General Practice, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Dieuwke
authors.initials: D
authors.lastname: Schiphof
authors.affiliation: Department of General Practice, Erasmus MC, Rotterdam, The Netherlands.|Department of Orthopaedics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Sita M
authors.initials: SM
authors.lastname: Bierma-Zeinstra
authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Richardson
authors.affiliation: Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham City Hospital, Nottingham, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Jenkins
authors.affiliation: Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham City Hospital, Nottingham, UK.|Arthritis Research UK Pain Centre, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Doherty
authors.affiliation: Academic Rheumatology, Clinical Sciences Building, University of Nottingham, Nottingham City Hospital, Nottingham, UK.|Arthritis Research UK Pain Centre, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
mesh_terms: D019643:Arthroplasty, Replacement / Q000009:adverse effects*; D055106:Genome-Wide Association Study; D006801:Humans; D009437:Neuralgia / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051571:Protein Kinase C-alpha / Q000235:genetics*
chemical_list: C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha