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Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis
  1. A-M Sims1,2,
  2. A E Timms2,
  3. J Bruges-Armas3,
  4. R Burgos-Vargas4,
  5. C-T Chou5,
  6. T Doan1,
  7. A Dowling1,
  8. R N Fialho3,
  9. P Gergely6,
  10. D D Gladman7,
  11. R Inman7,
  12. M Kauppi8,
  13. K Kaarela8,
  14. K Laiho8,9,
  15. W Maksymowych10,
  16. J J Pointon2,
  17. P Rahman11,
  18. J D Reveille12,
  19. R Sorrentino13,
  20. J Tuomilehto14,
  21. G Vargas-Alarcon15,
  22. B P Wordsworth1,
  23. H Xu16,17,
  24. M A Brown1,2,
  25. on behalf of the International Genetics of Ankylosing Spondylitis
  1. 1
    Diamantina Institute of Cancer, Immunology and Metabolic Medicine, University of Queensland, Brisbane, Quensland, Australia
  2. 2
    Botnar Research Centre, University of Oxford, Oxford, UK
  3. 3
    SEEBMO/The Azores, IBMC – Molecular and Cellular Biology Institute, University of Porto, Porto, Portugal
  4. 4
    Hospital General de México and Universidad Nacional Autónoma de México, Mexico City, Mexico
  5. 5
    Veterans General Hospital, Taipei, Taiwan
  6. 6
    National Institute of Rheumatology and Physiotherapy, Budapest, Hungary
  7. 7
    University of Toronto, Toronto, Ontario, Canada
  8. 8
    Rheumatism Foundation Hospital, Heinola, Finland
  9. 9
    University of Tampere, Medical School, Department of Musculoskeletal Medicine, Tampere, Finland
  10. 10
    University of Alberta, Edmonton, Alberta, Canada
  11. 11
    Memorial University, St John’s, Newfoundland, Canada
  12. 12
    The University of Texas, Austin, Texas, USA
  13. 13
    Department of Cell Biology and Development, University “La Sapienza”, Rome, Italy
  14. 14
    National Public Health Institute, Helsinki, Finland
  15. 15
    Instituto Nacional de Cardíología Ignacio Chávez, Mexico City, Mexico
  16. 16
    The Queensland Institute of Medical Research, Brisbane, Queensland, Australia
  17. 17
    Changzheng Hospital, The Second Military Medical University, Shanghai, China
  1. Professor M A Brown, Diamantina Institute of Cancer, Immunology and Metabolic Medicine University of Queensland Princess, Ipswich Road Woolloongabba, Brisbane, Queensland, Australia; matt.brown{at}


Objectives: The aim of the current study was to determine the contribution of interleukin (IL)1 gene cluster polymorphisms previously implicated in susceptibility for ankylosing spondylitis (AS) to AS susceptibility in different populations worldwide.

Methods: Nine polymorphisms in the IL1 gene cluster members IL1A (rs2856836, rs17561 and rs1894399), IL1B (rs16944), IL1F10 (rs3811058) and IL1RN (rs419598, the IL1RA VNTR, rs315952 and rs315951) were genotyped in 2675 AS cases and 2592 healthy controls recruited in 12 different centres in 10 countries. Association of variants with AS was tested by Mantel–Haenszel random effects analysis.

Results: Strong association was observed with three single nucleotide polymorphisms (SNPs) in the IL1A gene (rs2856836, rs17561, rs1894399, p = 0.0036, 0.000019 and 0.0003, respectively). There was no evidence of significant heterogeneity of effects between centres, and no evidence of non-combinability of findings. The population attributable risk fraction of these variants in Caucasians is estimated at 4–6%.

Conclusions: This study confirms that IL1A is associated with susceptibility to AS. Association of the other IL1 gene complex members could not be excluded in specific populations. Prospective meta-analysis is a useful tool in confirmation studies of genes associated with complex genetic disorders such as AS, providing sufficiently large sample sizes to produce robust findings often not achieved in smaller individual cohorts.

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  • Funding: This study was funded by the Arthritis Research Campaign (UK) and by National Institute of Arthritis and Musculoskeletal and Skin Diseases grants 1PO1-052915-01, RO1 AR046208 and RO1-AR048465. MAB was funded by the National Health and Medical Research Council (Australia).

  • Competing interests: None declared.

  • Ethics approval: All cohorts had been recruited with the approval of their local ethics committees.