Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1

Adrian Cortes, Sara L. Pulit, Paul J. Leo, Jenny J. Pointon, Philip C. Robinson, Michael H. Weisman, Michael Ward, Lianne S. Gensler, Xiaodong Zhou, Henri-Jean Garchon, Gilles Chiocchia, Johannes Nossent, Benedicte A. Lie, Øystein Førre, Jaakko Tuomilehto, Kari Laiho, Linda A. Bradbury, Dirk Elewaut, Ruben Burgos-Vargas, Simon Stebbings, Louise Appleton, Claire Farrah, Jonathan Lau, Nigil Haroon, Juan Mulero, Francisco J. Blanco, Miguel A. Gonzalez-Gay, C Lopez-Larrea, Paul Bowness, Karl Gaffney, Hill Gaston, Dafna D. Gladman, Proton Rahman, Walter P. Maksymowych, J. Bart A. Crusius, Irene E. van der Horst-Bruinsma, Raphael Valle-Oñate, Consuelo Romero-Sánchez, Inger Myrnes Hansen, Fernando M. Pimentel-Santos, Robert D. Inman, Javier Martin, Maxime Breban, Bryan Paul Wordsworth, John D. Reveille, David M. Evans, Paul I.W. de Bakker and Matthew A. Brown ()
Additional contact information
Adrian Cortes: University of Queensland Diamantina Institute, Princess Alexandra Hospital
Sara L. Pulit: Center for Molecular Medicine, University Medical Center Utrecht
Paul J. Leo: University of Queensland Diamantina Institute, Princess Alexandra Hospital
Jenny J. Pointon: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre
Philip C. Robinson: University of Queensland Diamantina Institute, Princess Alexandra Hospital
Michael H. Weisman: Cedars-Sinai Medical Center
Michael Ward: Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health
Lianne S. Gensler: University of California
Xiaodong Zhou: University of Texas Health Science Center at Houston
Henri-Jean Garchon: INSERM UMR 1173, Université de Versailles Saint Quentin en Yvelines, Laboratoire d’excellence Inflamex
Gilles Chiocchia: INSERM UMR 1173, Université de Versailles Saint Quentin en Yvelines, Laboratoire d’excellence Inflamex
Johannes Nossent: School of Medicine, University of Western Australia
Benedicte A. Lie: University of Oslo and Oslo University Hospital
Øystein Førre: Oslo University Hospital, and University of Oslo
Jaakko Tuomilehto: National Institute for Health and Welfare
Kari Laiho: Paijat-Hame Central Hospital
Linda A. Bradbury: University of Queensland Diamantina Institute, Princess Alexandra Hospital
Dirk Elewaut: Gent University Hospital
Ruben Burgos-Vargas: Hospital General de Mexico and Universidad Nacional Autonoma de Mexico
Simon Stebbings: Dunedin School of Medicine, University of Otago
Louise Appleton: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre
Claire Farrah: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre
Jonathan Lau: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre
Nigil Haroon: Toronto Western Hospital, University of Toronto
Juan Mulero: Hospital Puerta de Hierro
Francisco J. Blanco: Complejo Hospitalario La Coruña, INIBIC
Miguel A. Gonzalez-Gay: Hospital Marques de Valcecillas, IFIMAV
C Lopez-Larrea: Hospital Universitario Central de Asturias
Paul Bowness: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre
Karl Gaffney: Norfolk and Norwich University Hospital
Hill Gaston: University of Cambridge, Addenbrookes Hospital
Dafna D. Gladman: University of Toronto
Proton Rahman: Memorial University of Newfoundland
Walter P. Maksymowych: University of Alberta
J. Bart A. Crusius: Laboratory of Immunogenetics, VU University Medical Center
Irene E. van der Horst-Bruinsma: VU University Medical Centre
Raphael Valle-Oñate: Hospital Militar Central/Universidad de La Sabana
Consuelo Romero-Sánchez: Hospital Militar Central/Universidad de La Sabana
Inger Myrnes Hansen: Helgelandssykehuset, 8613
Fernando M. Pimentel-Santos: Chronic Diseases Research Centre (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa
Robert D. Inman: Toronto Western Hospital, University of Toronto
Javier Martin: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones–Científicas
Maxime Breban: INSERM UMR 1173, Université de Versailles Saint Quentin en Yvelines, Laboratoire d’excellence Inflamex
Bryan Paul Wordsworth: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre
John D. Reveille: University of Texas Health Science Center at Houston
David M. Evans: University of Queensland Diamantina Institute, Princess Alexandra Hospital
Paul I.W. de Bakker: Center for Molecular Medicine, University Medical Center Utrecht
Matthew A. Brown: University of Queensland Diamantina Institute, Princess Alexandra Hospital

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: Abstract Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

Date: 2015
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DOI: 10.1038/ncomms8146

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