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The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance
  1. Ana M Valdes1,
  2. Evangelos Evangelou2,
  3. Hanneke J M Kerkhof3,4,
  4. Agu Tamm5,
  5. Sally A Doherty6,
  6. Kalle Kisand5,7,
  7. Ann Tamm8,
  8. Irina Kerna5,
  9. Andre Uitterlinden3,4,
  10. Albert Hofman8,
  11. Fernando Rivadeneira3,4,
  12. Cyrus Cooper10,11,
  13. Elaine M Dennison10,
  14. Weiya Zhang6,
  15. Kenneth R Muir12,
  16. John P A Ioannidis2,
  17. Margaret Wheeler6,
  18. Rose A Maciewicz13,
  19. Joyce B van Meurs3,4,
  20. Nigel K Arden10,11,
  21. Tim D Spector1,
  22. Michael Doherty6
  1. 1Department of Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, King's College London, London, UK
  2. 2Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
  3. 3Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
  4. 4Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands
  5. 5Department of Internal Medicine, University of Tartu, Tartu, Estonia
  6. 6Academic Rheumatology, University of Nottingham, City Hospital Nottingham, Nottingham, UK
  7. 7Immunology Group, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia
  8. 8Department of Sports Medicine and Rehabilitation, University of Tartu, Tartu, Estonia
  9. 9Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  10. 10MRC Epidemiology Resource Centre, Southampton, UK
  11. 11Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK
  12. 12Health Sciences Research Institute, Warwick Medical School, University of Warwick, Warwick, UK
  13. 13Respiratory and Inflammation Research Area, AstraZeneca, Charnwood R&D, Loughborough, UK
  1. Correspondence to Dr Ana M Valdes, Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas Hospital, London SE1 7EH, UK; ana.valdes{at}

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Osteoarthritis of the knee is a major cause of pain, disability and the use of healthcare resources among middle-aged and older people.1 Although osteoarthritis is multifactorial, it is known to have a significant genetic contribution and a number of studies have attempted to dissect such a contribution (see Valdes and Spector2 for review).

The GDF5 gene encodes the growth differentiation factor 5, a bone morphogenetic protein involved in joint formation, expressed in different joint structures, which has been shown to ameliorate tendon, ligament and bone healing after trauma in mice.3 4

A promoter polymorphism (rs143383) in GDF5 has been found to be strongly associated with both hip and knee osteoarthritis in Asian individuals,4 and is the most widely replicated genetic association with knee osteoarthritis, although much less so for hip and hand osteoarthritis.5 This variant is functional, with the lower gene expression variant having increased genetic risk.4

A large-scale meta-analysis reported the association of the major (T) allele with knee osteoarthritis achieved OR 1.15 p=9.7×10−7 and achieved p=9×10−5 (OR 1.13, 95% CI 1.06 to 1.20) when Asian subjects were excluded.5

The genome-wide statistical significance level of p<5×10−8 is increasingly …

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