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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 al 6 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 …
Handling editor Josef S Smolen
Contributors All authors contributed to the design and/or acquisition and analysis of data. All authors drafted or reviewed the manuscript critically and gave final approval for the version submitted. All authors agree to be accountable for all aspects of the submitted work.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data will be made available on reasonable request.
Collaborators International Genetics of Ankylosing Spondylitis (IGAS) Consortium: Paul Bowness, Paul Wordsworth: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford, UK; Maxime Breban: INSERM UMR 1173, Université de Versailles Saint Quentin en Yvelines, Laboratoire d’excellence Inflamex, Saint-Quentn-En-Yvelines, France; Matthew Brown: School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia; Robert Colbert: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA; Adrian Cortes: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; Bart Crusius: Department of Medical Microbiology and Infection Control, Laboratory of Immunogenetics, VU University Medical Center, Amsterdam, The Netherlands; Jing Cui, Soumya Raychaudhuri: Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Dirk Elewaut: Department of Rheumatology, Gent University Hospital, Gent, Belgium; David Evans: University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia; Øystein Førre: Department of Rheumatology, Oslo University Hospital, and University of Oslo, Oslo, Norway; Dafna Gladman: Division of Rheumatology, University of Toronto, Toronto, Canada; Nigil Haroon, Robert Inman: Division of Rheumatology, Toronto Western Hospital, University of Toronto, Toronto, Canada; Benedicte Lie: Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway; Carlos Lopez-Larrea: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain; Walter Maksymowych: Department of Medicine, University of Alberta, Alberta, Canada; Javier Martin: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones-Científicas, Granada, Spain; Hans Nossent: School of Medicine, University of Western Australia, Perth, Australia Proton Rahman: Memorial University of Newfoundland, Newfoundland, Canada; John Reveille: Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA; Fernando Santos: Chronic Diseases Research Centre (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal; Simon Stebbings: Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand; Jaakko Tuomilehto: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; Rafael Valle-Oñate: Spondyloarthropaty Group-Division of Rheumatology, Hospital Militar Central/Universidad de La Sabana, Bogotá, NA, Colombia; Irene van der Horst-Bruinsma: Department of Rheumatology, VU University Medical Centre, Amsterdam, Netherlands; Michael Weisman: Department of Medicine/Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.