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Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis
  1. A Cortes1,
  2. W P Maksymowych2,
  3. B P Wordsworth3,
  4. R D Inman4,
  5. P Danoy1,
  6. P Rahman5,
  7. M A Stone6,
  8. M Corr7,
  9. Lianne S Gensler8,
  10. D Gladman9,10,11,
  11. A Morgan12,
  12. H Marzo-Ortega12,
  13. M M Ward13,
  14. SPARCC (Spondyloarthritis Research Consortium of Canada), TASC (Australo-Anglo-American Spondyloarthritis Consortium),,
  15. T J Learch14,
  16. J D Reveille15,
  17. M A Brown1,
  18. M H Weisman14
  1. 1University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  2. 2Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
  3. 3NIHR Oxford Musculoskeletal Biomedical Research Unit, Oxford Comprehensive Biomedical Research Centre, Nuffield Orthopaedic Centre, Oxford, UK
  4. 4Division of Rheumatology, Toronto Western Hospital, Toronto, Canada
  5. 5Memorial University of Newfoundland, St. Johns, Newfoundland, Canada
  6. 6Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK
  7. 7School of Medicine, University of San Diego, San Diego, California, USA
  8. 8Department of Medicine (Division of Rheumatology), University of California, San Francisco, USA
  9. 9Division of Rheumatology, University of Toronto, Toronto, Ontario, Canada
  10. 10Toronto Western Research Institute, Toronto, Canada
  11. 11Psoriatic Arthritis Program, University Health Network
  12. 12NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds Teaching Hospitals Trust, Leeds, UK
  13. 13National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
  14. 14Cedars-Sinai Medical Center, Los Angeles, California, USA
  15. 15Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA
  1. Correspondence to Professor Matthew A Brown, University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Road, Woolloongabba, QLD 4102, Australia; matt.brown{at}uq.edu.au

Abstract

Objective To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS).

Method We studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon–intron boundaries, and 5 kb flanking DNA in the 5′ and 3′ UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting p<0.05 were genotyped in a further cohort of 830 AS cases; results were analysed both separately and in combination with the discovery phase data. Association was tested by contingency tables after separating the samples into ‘mild’ and ‘severe’ groups, defined as the bottom and top 40% by mSASSS, adjusted for gender and disease duration.

Results Experiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10−5), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10−3). There was no observed association between radiographic severity and HLA-B*27.

Conclusions These findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.

Keywords
  • Ankylosing spondylitis
  • genetic association study
  • x-ray

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