title: Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1.
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.
authors.affiliation: University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Cortes
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584, The Netherlands.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Pulit
authors.affiliation: University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.affiliation: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, UK.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Pointon
authors.affiliation: University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Robinson
authors.affiliation: Department of Medicine/Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Weisman
authors.affiliation: Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-1468, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ward
authors.affiliation: Department of Medicine/Rheumatology, University of California, San Francisco, California 94143, USA.
authors.forename: Lianne S
authors.initials: LS
authors.lastname: Gensler
authors.affiliation: Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 1] INSERM UMR 1173, Université de Versailles Saint Quentin en Yvelines, Laboratoire d'excellence Inflamex, Saint-Quentn-En-Yvelines 78180, France [2] Genetics Division, Hôpital Ambroise Paré, AP-HP, and Université de Versailles Saint Quentin en Yvelines, Boulogne-Billancourt 78180, France.
authors.forename: Henri-Jean
authors.initials: HJ
authors.lastname: Garchon
authors.affiliation: INSERM UMR 1173, Université de Versailles Saint Quentin en Yvelines, Laboratoire d'excellence Inflamex, Saint-Quentn-En-Yvelines 78180, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.affiliation: 1] School of Medicine, University of Western Australia, Perth, WA 6009, Australia [2] Department of Rheumatology, Sir Charles Gairdner Hospital, Perth, WA 6009, Australia.
authors.forename: Johannes
authors.identifier: 0000000228337997
authors.initials: J
authors.lastname: Nossent
authors.affiliation: 1] Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo 0310, Norway [2] Department of Immunology, Oslo University Hospital, Oslo 0310, Norway.
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.affiliation: Department of Rheumatology, Oslo University Hospital, and University of Oslo, Oslo 0310, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Førre
authors.affiliation: 1] Department of Chronic Disease Prevention, National Institute for Health and Welfare, 00271 Helsinki, Finland [2] Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria [3] Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.affiliation: Department of Medicine, Paijat-Hame Central Hospital, Lahti, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Laiho
authors.affiliation: University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Bradbury
authors.affiliation: 1] Department of Rheumatology, Gent University Hospital, Gent 9052, Belgium [2] VIB Inflammation Research Center, Ghent University, Gent 9052, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.affiliation: Department of Rheumatology, Hospital General de Mexico and Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico.
authors.forename: Ruben
authors.initials: R
authors.lastname: Burgos-Vargas
authors.affiliation: Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
authors.forename: Simon
authors.initials: S
authors.lastname: Stebbings
authors.affiliation: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Appleton
authors.affiliation: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Farrah
authors.affiliation: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lau
authors.affiliation: Division of Rheumatology, Toronto Western Hospital, University of Toronto, Toronto M5T2S8, Canada.
authors.forename: Nigil
authors.initials: N
authors.lastname: Haroon
authors.affiliation: Department of Rheumatology, Hospital Puerta de Hierro, Madrid 28222, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Mulero
authors.affiliation: Department of Rheumatology, Complejo Hospitalario La Coruña, INIBIC, La Coruña 15006, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Blanco
authors.affiliation: Department of Rheumatology, Hospital Marques de Valcecillas, IFIMAV, Santander 39008, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gonzalez-Gay
authors.affiliation: 1] Department of Immunology, Hospital Universitario Central de Asturias, Oviedo 33011, Spain [2] Fundación Renal 'Iñigo Álvarez de Toledo', Madrid 33011, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Lopez-Larrea
authors.affiliation: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Bowness
authors.affiliation: Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: Gaffney
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 0SP, UK.
authors.forename: Hill
authors.initials: H
authors.lastname: Gaston
authors.affiliation: 1] Division of Rheumatology, University of Toronto, Toronto, ON M4N 3M5, Canada [2] Toronto Western Research Institute, Toronto ON M4N 3M5, Canada [3] Psoriatic Arthritis Program, University Health Network, Toronto ON M4N 3M5, Canada.
authors.forename: Dafna D
authors.initials: DD
authors.lastname: Gladman
authors.affiliation: Memorial University of Newfoundland, Newfoundland NL A1B 3X9, Canada.
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
authors.affiliation: Department of Medicine, University of Alberta, Alberta T6G 2R7, Canada.
authors.forename: Walter P
authors.initials: WP
authors.lastname: Maksymowych
authors.affiliation: Department of Medical Microbiology and Infection Control, Laboratory of Immunogenetics, VU University Medical Center, Amsterdam 1081 BT, The Netherlands.
authors.forename: J Bart A
authors.initials: JB
authors.lastname: Crusius
authors.affiliation: Department of Rheumatology, VU University Medical Centre, Amsterdam 1081 BT, Netherlands.
authors.forename: Irene E
authors.initials: IE
authors.lastname: van der Horst-Bruinsma
authors.affiliation: Spondyloarthropaty Group-Division of Rheumatology, Hospital Militar Central/Universidad de La Sabana, Transversal 3 # 49-00, Bogotá, NA, Colombia.
authors.forename: Raphael
authors.initials: R
authors.lastname: Valle-Oñate
authors.affiliation: Spondyloarthropaty Group-Division of Rheumatology, Hospital Militar Central/Universidad de La Sabana, Transversal 3 # 49-00, Bogotá, NA, Colombia.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Romero-Sánchez
authors.affiliation: Helgelandssykehuset, 8613 Mo i Rana, Norway.
authors.forename: Inger Myrnes
authors.initials: IM
authors.lastname: Hansen
authors.affiliation: Chronic Diseases Research Centre (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa 1169-056, Portugal.
authors.forename: Fernando M
authors.initials: FM
authors.lastname: Pimentel-Santos
authors.affiliation: Division of Rheumatology, Toronto Western Hospital, University of Toronto, Toronto M5T2S8, Canada.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Inman
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones-Científicas, Granada 18100, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.affiliation: 1] INSERM UMR 1173, Université de Versailles Saint Quentin en Yvelines, Laboratoire d'excellence Inflamex, Saint-Quentn-En-Yvelines 78180, France [2] Division of Rheumatology, Hôpital Ambroise Paré, AP-HP, and Université de Versailles Saint Quentin en Yvelines, Boulogne-Billancourt 92100, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Breban
authors.affiliation: NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, UK.
authors.forename: Bryan Paul
authors.initials: BP
authors.lastname: Wordsworth
authors.affiliation: Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Reveille
authors.affiliation: 1] University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia [2] MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK [3] School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: 1] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584, The Netherlands [2] Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
mesh_terms: D000626:Aminopeptidases / Q000235:genetics*; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000235:genetics*; D059947:HLA-B40 Antigen / Q000235:genetics*; D006801:Humans; D008285:Major Histocompatibility Complex; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000209:etiology*
chemical_list: D015796:HLA-B27 Antigen; D059947:HLA-B40 Antigen; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human