title: Ankylosing spondylitis is associated with the anthrax toxin receptor 2 gene (ANTXR2).
abstract: OBJECTIVE
  ANTXR2 variants have been associated with ankylosing spondylitis (AS) in two previous genome-wide association studies (GWAS) (p∼9×10(-8)). However, a genome-wide significant association (p<5×10(-8)) was not observed. We conducted a more comprehensive analysis of ANTXR2 in an independent UK sample to confirm and refine this association.
  
  
  METHODS
  A replication study was carried out with 2978 cases and 8365 controls. Then, these were combined with non-overlapping samples from the two previous GWAS in a meta-analysis. Human leukocyte antigen (HLA)-B27 stratification was also performed to test for ANTXR2-HLA-B27 interaction.
  
  
  RESULTS
  Out of nine single nucleotide polymorphisms (SNP) in the study, five SNPs were nominally associated (p<0.05) with AS in the replication dataset. In the meta-analysis, eight SNPs showed evidence of association, the strongest being with rs12504282 (OR=0.88, p=6.7×10(-9)). Seven of these SNPs showed evidence for association in the HLA-B27-positive subgroup, but none was associated with HLA-B27-negative AS. However, no statistically significant interaction was detected between HLA-B27 and ANTXR2 variants.
  
  
  CONCLUSIONS
  ANTXR2 variants are clearly associated with AS. The top SNPs from two previous GWAS (rs4333130 and rs4389526) and this study (rs12504282) are in strong linkage disequilibrium (r(2)≥0.76). All are located near a putative regulatory region. Further studies are required to clarify the role played by these ANTXR2 variants in AS.
authors.affiliation: National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: T
authors.initials: T
authors.lastname: Karaderi
authors.affiliation: National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: S M
authors.initials: SM
authors.lastname: Keidel
authors.affiliation: National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: J J
authors.initials: JJ
authors.lastname: Pointon
authors.affiliation: National Institute for Health Research Oxford Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: L H
authors.initials: LH
authors.lastname: Appleton
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: M A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: National Institute for Health Research Oxford Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK National Institute for Health Research Oxford Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.
authors.forename: B P
authors.initials: BP
authors.lastname: Wordsworth
mesh_terms: D016022:Case-Control Studies; D002648:Child; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015796:HLA-B27 Antigen / Q000032:analysis; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D018000:Receptors, Peptide / Q000235:genetics*; D013167:Spondylitis, Ankylosing / Q000235:genetics*
chemical_list: C447150:ANTXR2 protein, human; D015796:HLA-B27 Antigen; D018000:Receptors, Peptide
keywords: Ankylosing Spondylitis; Epidemiology; Gene Polymorphism; Inflammation; Spondyloarthritis