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Imputation-based analysis of MICA alleles in the susceptibility to ankylosing spondylitis
  1. Adrian Cortes1,2,
  2. Dafna Gladman3,
  3. Soumya Raychaudhuri4,
  4. Jing Cui4,
  5. Lawrie Wheeler5,
  6. Matthew A Brown5
  7. International Genetics of Ankylosing Spondylitis Consortium (IGAS)
    1. 1Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford, UK
    2. 2Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
    3. 3Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada
    4. 4Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
    5. 5Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Queensland, Australia
    1. Correspondence to Professor Matthew A Brown, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT) at Translational Research Institute, Brisbane, Queensland 4102, Australia; matt.brown{at}qut.edu.au

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    Ankylosing spondylitis (AS) susceptibility is strongly correlated with genetic variation within the major histocompatibility complex (MHC), and the class I HLA-B*27 allele confers the major genetic risk factor to AS.1 Furthermore, strong evidence for additional alleles in the MHC has been observed which affect susceptibility independently from the HLA-B*27 allele, either by direct genotyping in candidate gene studies2 or through large-scale imputation-driven association studies.3 4 We have previously identified variants in both class I and II which affect susceptibility to AS through imputation of classical HLA alleles.4

    The MICA gene is encoded 46 kbps from HLA-B and previous studies have reported genetic variants within this locus to affect susceptibility to AS and other inflammatory diseases.5 In particular, in Annals of Rheumatic Diseases, Zhou et al6 evaluated the association of MICA variants with susceptibility to AS in cohorts from North America and China. This study found that the allele MICA*007:01 was strongly associated with risk of AS independently of HLA-B*27, with an association observed in the HLA-B27-negative cohort (US cohort OR=9.12, p=4.28×10–8; Chinese cohort OR=42.2, p=9.35×10–7). Weak protective associations with other MICA alleles were noted, likely because of the over-representation of the risk allele MICA*007:01.

    Having previously observed extremely strong linkage disequilibrium (LD) between HLA-B and MICA single nucleotide …

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