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The genetic associations of acute anterior uveitis and their overlap with the genetics of ankylosing spondylitis

Genes & Immunity volume 17, pages 46–51 (2016)Cite this article

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Abstract

Acute anterior uveitis (AAU) involves inflammation of the iris and ciliary body of the eye. It occurs both in isolation and as a complication of ankylosing spondylitis (AS). It is strongly associated with HLA-B*27, but previous studies have suggested that further genetic factors may confer additional risk. We sought to investigate this using the Illumina Exomechip microarray, to compare 1504 cases with AS and AAU, 1805 with AS but no AAU and 21 133 healthy controls. We also used a heterogeneity test to test the differences in effect size between AS with AAU and AS without AAU. In the analysis comparing AS+AAU+ cases versus controls, HLA-B*27 and HLA-A*02:01 were significantly associated with the presence of AAU (P<10−300 and P=6 × 10−8, respectively). Secondary independent association with PSORS1C3 (P=4.7 × 10−5) and TAP2 (P=1.1 × 10−5) were observed in the major histocompatibility complex. There was a new suggestive association with a low-frequency variant at zinc-finger protein 154 in the AS without AAU versus control analysis (zinc-finger protein 154 (ZNF154), P=2.2 × 10−6). Heterogeneity testing showed that rs30187 in ERAP1 has a larger effect on AAU compared with that in AS alone. These findings also suggest that variants in ERAP1 have a differential impact on the risk of AAU when compared with AS, and hence the genetic risk for AAU differs from AS.

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Acknowledgements

We acknowledge all patients who donated their DNA. PR was funded by the National Health and Medical Research Council (NHMRC) of Australia and is currently funded by the ARA-RACP-Starr Research Fellowship. MAB is supported by a Senior Principal Research Fellowship of the NHMRC. The AOGC ExomeChip genotyping was funded by NHMRC Project Grant 1032571 (ELD). The AOGC cohort collection was funded by NHMRC Project Grant 511132. Additional funding was provided by the NIHR Oxford Comprehensive Biomedical Research Centre (immunity and inflammation theme A93081), Arthritis Research UK (Grants 19536 and 18797), the NIHR Thames Valley collaborative research network and the National Ankylosing Spondylitis Society (UK).

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Authors and Affiliations

  1. Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia

    P C Robinson

  2. University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, QLD, Australia

    P C Robinson, P J Leo, J Harris, K Cremin, L A Bradbury, D M Evans, E L Duncan & M A Brown

  3. Department of Rheumatology, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia

    P C Robinson

  4. National Institute for Health Research (NIHR) Oxford Musculoskeletal Biomedical Research Unit and Comprehensive Biomedical Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK

    J J Pointon & B P Wordsworth

  5. Department of Medicine, University of Otago, Dunedin, New Zealand

    S Stebbings

  6. Department of Medicine, University of Otago, Wellington, New Zealand

    A A Harrison

  7. Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Herston, QLD, Australia

    E L Duncan

  8. School of Medicine, Faculty of Medicine and Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

    E L Duncan

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Consortia

Wellcome Trust Case Control Consortium

  • Peter Donnelly (Chair)
  • , Ines Barroso (Deputy Chair)
  • , Jenefer M Blackwell
  • , Elvira Bramon
  • , Matthew A Brown
  • , Juan P Casas
  • , Aiden Corvin
  • , Panos Deloukas
  • , Audrey Duncanson
  • , Janusz Jankowski
  • , Hugh S Markus
  • , Christopher G Mathew
  • , Colin NA Palmer
  • , Robert Plomin
  • , Anna Rautanen
  • , Stephen J Sawcer
  • , Richard C Trembath
  • , Ananth C Viswanathan
  • , Nicholas W Wood
  • , Chris CA Spencer
  • , Gavin Band
  • , Céline Bellenguez
  • , Colin Freeman
  • , Garrett Hellenthal
  • , Eleni Giannoulatou
  • , Matti Pirinen
  • , Richard Pearson
  • , Amy Strange
  • , Zhan Su
  • , Damjan Vukcevic
  • , Peter Donnelly
  • , Cordelia Langford
  • , Sarah E Hunt
  • , Sarah Edkins
  • , Rhian Gwilliam
  • , Hannah Blackburn
  • , Suzannah J Bumpstead
  • , Serge Dronov
  • , Matthew Gillman
  • , Emma Gray
  • , Naomi Hammond
  • , Alagurevathi Jayakumar
  • , Owen T McCann
  • , Jennifer Liddle
  • , Simon C Potter
  • , Radhi Ravindrarajah
  • , Michelle Ricketts
  • , Matthew Waller
  • , Paul Weston
  • , Sara Widaa
  • , Pamela Whittaker
  • , Ines Barroso
  • , Panos Deloukas
  • , Christopher G Mathew (Chair)
  • , Jenefer M Blackwell
  • , Matthew A Brown
  • , Aiden Corvin
  •  & Chris C A Spencer

Australasian Osteoporosis Genetics Consortium (AOGC)

  • Eugene McCloskey
  • , John Eisman
  • , Graeme Jones
  • , Geoff Nicholson
  • , Richard Eastell
  • , Philip Sambrook
  • , Richard Prince
  • , Elaine Dennison
  • , Ian Reid
  •  & John Wark

Corresponding author

Correspondence to M A Brown.

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The authors declare no conflict of interest.

Additional information

Membership of Wellcome Trust Case Control Consortium 2 (WTCCC2) Management committee: Peter Donnelly (Chair)1,2, Ines Barroso (Deputy Chair)3, Jenefer M Blackwell4,5, Elvira Bramon6, Matthew A Brown7, Juan P Casas8, Aiden Corvin9, Panos Deloukas3, Audrey Duncanson10, Janusz Jankowski11, Hugh S Markus12, Christopher G Mathew13, Colin NA Palmer14, Robert Plomin15, Anna Rautanen1, Stephen J Sawcer16, Richard C Trembath13, Ananth C Viswanathan17, Nicholas W Wood18. Data and analysis group: Chris CA Spencer1, Gavin Band1, Céline Bellenguez1, Colin Freeman1, Garrett Hellenthal1, Eleni Giannoulatou1, Matti Pirinen1, Richard Pearson1, Amy Strange1, Zhan Su1, Damjan Vukcevic1, Peter Donnelly1,2. DNA, genotyping, data QC and informatics group: Cordelia Langford3, Sarah E Hunt3, Sarah Edkins3, Rhian Gwilliam3, Hannah Blackburn3, Suzannah J Bumpstead3, Serge Dronov3, Matthew Gillman3, Emma Gray3, Naomi Hammond3, Alagurevathi Jayakumar3, Owen T McCann3, Jennifer Liddle3, Simon C Potter3, Radhi Ravindrarajah3, Michelle Ricketts3, Matthew Waller3, Paul Weston3, Sara Widaa3, Pamela Whittaker3, Ines Barroso3, Panos Deloukas3. Publications committee: Christopher G Mathew (Chair)13, Jenefer M Blackwell4,5, Matthew A Brown7, Aiden Corvin9, Chris C A Spencer1 1Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK; 2Department of Statistics, University of Oxford, Oxford OX1 3TG, UK; 3Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK; 4Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, 100 Roberts Road, Subiaco, WA 6008, Australia; 5Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge CB2 0XY, UK; 6Department of Psychosis Studies, NIHR Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King’s College London and The South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AF, UK; 7University of Queensland Diamantina Institute, Brisbane, QLD, Australia; 8Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT and Department of Epidemiology and Public Health, University College London WC1E 6BT, UK; 9Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Eire; 10Molecular and Physiological Sciences, The Wellcome Trust, London NW1 2BE, UK; 11Department of Oncology, Old Road Campus, University of Oxford, Oxford OX3 7DQ, UK, Digestive Diseases Centre, Leicester Royal Infirmary, Leicester LE7 7HH, UK and Centre for Digestive Diseases, Queen Mary University of London, London E1 2AD, UK; 12Clinical Neurosciences, St George’s University of London, London SW17 0RE, UK; 13King’s College London Department of Medical and Molecular Genetics, King’s Heath Partners, Guy’s Hospital, London SE1 9RT, UK; 14Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK; 15King’s College, London Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK; 16University of Cambridge Department of Clinical Neurosciences, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK; 17NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK; 18Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London WC1N 3BG, UK.

Membership of Australasian Osteoporosis Genetics Consortium (AOGC) contributing to ExomeChip samples Eugene McCloskey1, John Eisman2, Graeme Jones3, Geoff Nicholson4, Richard Eastell5, Philip Sambrook6 (deceased), Richard Prince7, Elaine Dennison8, Ian Reid9, John Wark10 1Academic Unit of Bone Metabolism, University of Sheffield, UK; 2Garvan Institute of Medical Research, University of New South Wales, Australia; 3Menzies Research Institute, University of Tasmania, Australia; 4Rural Clinical School, University of Queensland, Australia; 5Academic Unit of Bone Metabolism, Metabolic Bone Centre, University of Sheffield, UK; 6Kolling Institute, Royal North Shore Hospital, University of Sydney, Australia; 7School of Medicine and Pharmacology, University of Western Australia, Australia; 8Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, UK; 9Department of Medicine, University of Auckland, New Zealand; 10Department of Medicine, University of Melbourne, Australia.

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Robinson, P., Leo, P., Pointon, J. et al. The genetic associations of acute anterior uveitis and their overlap with the genetics of ankylosing spondylitis. Genes Immun 17, 46–51 (2016). https://doi.org/10.1038/gene.2015.49

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