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Nat Commun. 2015 May 21;6:7146. doi: 10.1038/ncomms8146.

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

Author information

1
University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
2
Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584, The Netherlands.
3
NIHR Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, UK.
4
Department of Medicine/Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
5
Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-1468, USA.
6
Department of Medicine/Rheumatology, University of California, San Francisco, California 94143, USA.
7
Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
8
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.
9
INSERM UMR 1173, Université de Versailles Saint Quentin en Yvelines, Laboratoire d'excellence Inflamex, Saint-Quentn-En-Yvelines 78180, France.
10
1] School of Medicine, University of Western Australia, Perth, WA 6009, Australia [2] Department of Rheumatology, Sir Charles Gairdner Hospital, Perth, WA 6009, Australia.
11
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.
12
Department of Rheumatology, Oslo University Hospital, and University of Oslo, Oslo 0310, Norway.
13
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.
14
Department of Medicine, Paijat-Hame Central Hospital, Lahti, Finland.
15
1] Department of Rheumatology, Gent University Hospital, Gent 9052, Belgium [2] VIB Inflammation Research Center, Ghent University, Gent 9052, Belgium.
16
Department of Rheumatology, Hospital General de Mexico and Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico.
17
Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
18
Division of Rheumatology, Toronto Western Hospital, University of Toronto, Toronto M5T2S8, Canada.
19
Department of Rheumatology, Hospital Puerta de Hierro, Madrid 28222, Spain.
20
Department of Rheumatology, Complejo Hospitalario La Coruña, INIBIC, La Coruña 15006, Spain.
21
Department of Rheumatology, Hospital Marques de Valcecillas, IFIMAV, Santander 39008, Spain.
22
1] Department of Immunology, Hospital Universitario Central de Asturias, Oviedo 33011, Spain [2] Fundación Renal 'Iñigo Álvarez de Toledo', Madrid 33011, Spain.
23
Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich NR4 7UY, UK.
24
Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 0SP, UK.
25
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.
26
Memorial University of Newfoundland, Newfoundland NL A1B 3X9, Canada.
27
Department of Medicine, University of Alberta, Alberta T6G 2R7, Canada.
28
Department of Medical Microbiology and Infection Control, Laboratory of Immunogenetics, VU University Medical Center, Amsterdam 1081 BT, The Netherlands.
29
Department of Rheumatology, VU University Medical Centre, Amsterdam 1081 BT, Netherlands.
30
Spondyloarthropaty Group-Division of Rheumatology, Hospital Militar Central/Universidad de La Sabana, Transversal 3 # 49-00, Bogotá, NA, Colombia.
31
Helgelandssykehuset, 8613 Mo i Rana, Norway.
32
Chronic Diseases Research Centre (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa 1169-056, Portugal.
33
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones-Científicas, Granada 18100, Spain.
34
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.
35
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.
36
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.

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.

PMID:
25994336
PMCID:
PMC4443427
DOI:
10.1038/ncomms8146
[Indexed for MEDLINE]
Free PMC Article

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