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Meta-analyses of genes modulating intracellular T3 bio-availability reveal a possible role for the DIO3 gene in osteoarthritis susceptibility
  1. Ingrid Meulenbelt1,
  2. Steffan D Bos1,2,
  3. Kay Chapman3,
  4. Ruud van der Breggen1,
  5. Jeanine J Houwing-Duistermaat4,
  6. Dennis Kremer1,
  7. Margreet Kloppenburg5,
  8. Andrew Carr3,
  9. Aspasia Tsezou6,
  10. Antonio González7,
  11. John Loughlin8,
  12. P Eline Slagboom1,2
  1. 1Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  2. 2The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden, The Netherlands
  3. 3Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Center, University of Oxford, Oxford, UK
  4. 4Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Department of Rheumatology and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Department of Biology and Genetics, University of Thessaly, Larissa, Greece
  7. 7Laboratorio Investigacion and Rheumatology Unit. Instituto Investigacion Sanitaria-Hospital Clinico Universitario Santiago, Spain
  8. 8Newcastle University, Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle, UK
  1. Correspondence to Dr Ingrid Meulenbelt, Section Molecular Epidemiology, Leiden University Medical Centre, Postzone S-05-P, PO Box 9600, 2300 RC Leiden, The Netherlands; i.meulenbelt{at}


Objective To study whether common genetic variants of the genes involved in the complex regulatory mechanism determining the intracellular bio-availability of T3 influence osteoarthritis onset.

Methods In total 17 genetic variants within the genes encoding WD40-repeat/SOCS-box protein 1, ubiquitin specific protease 33, thyroid hormone receptor α, deiodinase, iodothyronine, type III (DIO3) and Indian hedgehog were measured and associated with osteoarthritis in a meta-analyses in European populations from the UK, The Netherlands, Greece and Spain containing a total of 3252 osteoarthritis cases and 2132 controls.

Results The minor allele of the DIO3 variant rs945006 showed suggestive evidence for protective association in the overall meta-analyses, which was supported by individual osteoarthritis studies and osteoarthritis subtypes. The association appeared most significant in cases with knee and/or hip with an allelic OR of 0.81 (95% CI 0.70 to 0.930) with a nominal p value of 0.004 and a permutation-based corrected p value for multiple testing of 0.039.

Conclusion The findings suggest that the DIO3 gene modulates osteoarthritis disease risk; however, additional studies are necessary to replicate our findings. To elucidate the molecular mechanisms focus should be on the local adaptation to T3 availability either during the endochondral ossification process or during ageing of the articular cartilage.

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  • Funding This study was supported by the Leiden University Medical Centre and the Dutch Arthritis Association. Pfizer, Groton, CT, USA supported the inclusion of the GARP study. The genotypic work was supported by the EC framework 7 programme grant 200800, 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 and Netherlands Consortium for Healthy Aging both in the framework of the Netherlands Genomics Initiative. The contribution of the Santiago group to this project was financed by the Foundation Mutua Madrilena Madrid, Spain. The UK study was supported by Research into Ageing and by the Arthritis Research Campaign.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Dutch cases and controls: Leiden University Medical Center; UK cases and controls: University of Oxford; Spanish cases and controls: Instituto Investigacion Sanitaria-Hospital Clinico Universitario Santiago; Greek cases and controls: University of Thessaly.

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