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Testing the druggable endothelial differentiation gene 2 knee osteoarthritis genetic factor for replication in a wide range of sample collections
  1. R Dieguez-Gonzalez1,
  2. M Calaza1,
  3. D Shi2,3,
  4. I Meulenbelt4,
  5. J Loughlin5,
  6. A Tsezou6,
  7. J Dai2,
  8. K N Malizos7,8,
  9. E P Slagboom4,
  10. M Kloppenburg9,
  11. K Chapman10,
  12. Q Jiang2,3,
  13. D Kremer4,
  14. J J Gomez-Reino1,11,
  15. N Nakajima12,
  16. S Ikegawa12,
  17. A Gonzalez1
  1. 1
    Laboratorio Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario Santiago, Santiago de Compostela, Spain
  2. 2
    The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital (Affiliated to Medical School of Nanjing University), Nanjing, Jiangsu, China
  3. 3
    Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu, China
  4. 4
    Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  5. 5
    Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle-on-Tyne, UK
  6. 6
    Department of Biology and Genetics, University of Thessaly, Larissa, Greece
  7. 7
    Department of Orthopaedics, University of Thessaly, Larissa, Greece
  8. 8
    Institute for Biomedical Research and Technology, Larissa, Greece
  9. 9
    Department of Rheumatology & Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  10. 10
    Botnar Research Centre, University of Oxford, Oxford, UK
  11. 11
    Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain
  12. 12
    Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Tokyo, Japan
  1. A Gonzalez, Laboratorio de Investigacion 2, Hospital Clinico Universitario de Santiago, 15706-Santiago de Compostela, Spain; Antonio.Gonzalez.Martinez.Pedrayo{at}; anlugon{at}


Objectives: To replicate a previously reported association with osteoarthritis (OA) of the promoter single nucleotide polymorphism (SNP) rs10980705 in the endothelial differentiation gene 2 (EDG2).

Methods: Five collections of samples, four from Europe and one from China, were studied. They included patients with 3 OA phenotypes: 1501 with knee OA, 1497 with hip OA and 376 with generalised OA. A total of 2521 controls were also studied. Allele and genotype frequencies of the rs10980705 SNP were analysed in each individual sample collection and in pooled data. In addition, a meta-analysis to incorporate results from the original Japanese report was performed.

Results: The association of the rs10980705 SNP with knee OA was not replicated in any of the five sample collections studied or in their combined analysis (odds ratio (OR) 1.10, 95% CI 0.98 to 1.22; p = 0.10). Meta-analysis of all data, including the original Japanese study, did show association with knee OA (OR 1.15, 95% CI 1.06 to 1.26; p = 0.002) but the effect was accounted for by the Japanese data and was less significant than the original report. No association was found with hip OA or with generalised OA.

Conclusions: The original report of a promising genetic association between a druggable G-protein coupled receptor, EDG2, and knee OA has not been replicated. This lack of replication could be due to a modest effect of the promoter polymorphism that will require even larger studies (the winners curse) although a more pronounced effect in the Asian population vs Europeans cannot be excluded.

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  • Competing interests: None declared.

  • Funding: The contribution of the Santiago group to this project was financed by the Fundacion MMA (Madrid, Spain). The UK study was supported by Research into Ageing and by The Arthritis Research Campaign. The Leiden University Medical Centre, the Dutch Arthritis Association and Pfizer, Groton, Connecticut, USA supported the GARP study and controls. The genotyping of Leiden samples was supported by The Netherlands Organization of Scientific Research (MW 904-61-095, 911-03-016, 917 66344 and 911-03-012), Leiden University Medical Centre and the Centre of Medical System Biology (CMSB) in the framework of The Netherlands Genomics Initiative (NGI). The Nanjing group was supported by National Nature Science Foundation of China (3057874) (to DS and QJ) and Programme of Technology Development of Nanjing (200603001) (to DS and QJ).

  • Ethics approval: All samples were obtained after the donors had provided their informed consent and with the approval of the respective ethics committees.

  • ▸ Additional data (supplementary table 1) are published online only at