title: Association study of genes related to bone formation and resorption and the extent of radiographic change in ankylosing spondylitis.
abstract: OBJECTIVE
  To identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS).
  
  
  METHODS
  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.
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Cortes
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: W P
authors.initials: WP
authors.lastname: Maksymowych
authors.affiliation: NIHR Oxford Musculoskeletal Biomedical Research Unit, Oxford Comprehensive Biomedical Research Centre, Nuffield Orthopaedic Centre, Oxford, UK.
authors.forename: B P
authors.initials: BP
authors.lastname: Wordsworth
authors.affiliation: Division of Rheumatology, Toronto Western Hospital, Toronto, Canada.
authors.forename: R D
authors.initials: RD
authors.lastname: Inman
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Danoy
authors.affiliation: Memorial University of Newfoundland, St. Johns, Newfoundland, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Rahman
authors.affiliation: Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Stone
authors.affiliation: School of Medicine, University of San Diego, San Diego, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Corr
authors.affiliation: Department of Medicine (Division of Rheumatology), University of California, San Francisco, USA.
authors.forename: Lianne S
authors.initials: LS
authors.lastname: Gensler
authors.affiliation: Division of Rheumatology, University of Toronto, Toronto, Ontario, Canada Toronto Western Research Institute, Toronto, Canada Psoriatic Arthritis Program, University Health Network.
authors.forename: D
authors.initials: D
authors.lastname: Gladman
authors.affiliation: NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds Teaching Hospitals Trust, Leeds, UK.
authors.forename: A
authors.initials: A
authors.lastname: Morgan
authors.affiliation: NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds Teaching Hospitals Trust, Leeds, UK.
authors.forename: H
authors.initials: H
authors.lastname: Marzo-Ortega
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Ward
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Learch
authors.affiliation: Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Reveille
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Weisman
mesh_terms: D000328:Adult; D001862:Bone Resorption / Q000235:genetics*; D002574:Cervical Vertebrae / Q000000981:diagnostic imaging*; D051545:Cyclooxygenase 1 / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging*; D008297:Male; D008875:Middle Aged; D010012:Osteogenesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011859:Radiography; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics; D012720:Severity of Illness Index; D013167:Spondylitis, Ankylosing / Q000000981:diagnostic imaging* / Q000235:genetics*
chemical_list: D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human
keywords: Ankylosing spondylitis; genetic association study; x-ray