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A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype
  1. Anne-Marie Malfait1,
  2. Albert B Seymour2,
  3. Feng Gao2,
  4. Micky D Tortorella3,
  5. Marie-Pierre Hellio Le Graverand-Gastineau2,
  6. Linda S Wood2,
  7. Michael Doherty4,
  8. Sally Doherty4,
  9. Weiya Zhang4,
  10. Nigel K Arden5,
  11. Frances L Vaughn6,
  12. Paul E Leaverton6,7,
  13. Tim D Spector8,
  14. Deborah J Hart8,
  15. Rose A Maciewicz9,
  16. Kenneth R Muir10,
  17. Rosalina Das1,
  18. Robert E Sorge11,
  19. Susanna G Sotocinal11,
  20. Ara Schorscher-Petcu11,
  21. Ana M Valdes8,
  22. Jeffrey S Mogil11
  1. 1Department of Biochemistry/Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
  2. 2Department of Clinical Research, Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA
  3. 3Department of Drug Discovery, Guangzhou Institute for Biomedical Health, Guangzhou, China
  4. 4Department of Academic Rheumatology, University of Nottingham, Nottingham, UK
  5. 5NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK
  6. 6The Arthritis Research Institute of America, Clearwater, Florida, USA
  7. 7Department of Epidemiology and Biostatistics, College of Public Health, University of South Florida, Tampa, Florida, USA
  8. 8Twin Research Unit, King's College London, London UK
  9. 9Respiratory and Inflammation iMed, AstraZeneca, Charnwood R&D, Loughborough, UK
  10. 10Health Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry, UK
  11. 11Department of Psychology and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada
  1. Correspondence to Anne-Marie Malfait, Rush University Medical Center, 1611 W. Harrison Street, Suite 510, Chicago, IL 60612, USA; anne-marie_malfait{at}


Objectives The aim of this study was to assess if genetic variation in the PACE4 (paired amino acid converting enzyme 4) gene Pcsk6 influences the risk for symptomatic knee osteoarthritis (OA).

Methods Ten PCSK6 single nucleotide polymorphisms were tested for association in a discovery cohort of radiographic knee OA (n=156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout mice and wild-type C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P, pain behaviours in response to intrathecal substance P and pain behaviour in the abdominal constriction test.

Results In the discovery cohort of radiographic knee OA, an intronic single nucleotide polymorphism at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an OR=1.35 (95% CI 1.17 to 1.56; p=4.3×10−5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout mice were significantly protected against pain in a battery of algesiometric assays.

Conclusions These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why, in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.

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  • Competing interests None.

  • Ethics approval Ethics approval was granted by all the local ethics committees at the respective institutions, as stated in the manuscript.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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