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ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients
  1. Philip C Robinson1,2,
  2. Mary-Ellen Costello2,
  3. Paul Leo2,
  4. Linda A Bradbury2,
  5. Kelly Hollis2,
  6. Adrian Cortes2,
  7. Seunghun Lee3,
  8. Kyung Bin Joo3,
  9. Seung-Cheol Shim4,
  10. Michael Weisman5,
  11. Michael Ward6,
  12. Xiaodong Zhou7,
  13. Henri-Jean Garchon8,9,
  14. Gilles Chiocchia8,
  15. Johannes Nossent10,11,
  16. Benedicte A Lie12,13,
  17. Øystein Førre14,
  18. Jaakko Tuomilehto15,16,17,
  19. Kari Laiho18,
  20. Lei Jiang19,
  21. Yu Liu19,
  22. Xin Wu19,
  23. Dirk Elewaut20,21,
  24. Ruben Burgos-Vargas22,
  25. Lianne S Gensler23,
  26. Simon Stebbings24,
  27. Nigil Haroon25,
  28. Juan Mulero26,
  29. Jose Luis Fernandez-Sueiro27,
  30. Miguel A Gonzalez-Gay28,
  31. Carlos Lopez-Larrea29,30,
  32. Paul Bowness31,
  33. Karl Gafney32,
  34. John S Hill Gaston33,
  35. Dafna D Gladman34,35,36,
  36. Proton Rahman37,
  37. Walter P Maksymowych38,
  38. Huji Xu19,
  39. Irene E van der Horst-Bruinsma39,
  40. Chung-Tei Chou40,41,
  41. Raphael Valle-Oñate42,
  42. María Consuelo Romero-Sánchez42,
  43. Inger Myrnes Hansen43,
  44. Fernando M Pimentel-Santos44,
  45. Robert D Inman25,
  46. Javier Martin45,
  47. Maxime Breban8,46,
  48. David Evans2,47,48,
  49. John D Reveille7,
  50. Tae-Hwan Kim3,
  51. B Paul Wordsworth49,
  52. Matthew A Brown2
  1. 1Centre for Neurogenetics and Statistical Genomics, Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
  2. 2The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  3. 3Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
  4. 4Department of Medicine, Division of Rheumatology, Eulji University Hospital, Daejeon, Republic of Korea
  5. 5Department of Medicine/Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA
  6. 6National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA
  7. 7Department of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA
  8. 8INSERM U1173, UFR Simone Veil, Versailles-Saint-Quentin University, Laboratoire d'Excellence INFLAMEX, France
  9. 9Genetics Division, Ambroise Paré Hospital (AP-HP), Boulogne-Billancourt, Paris, France
  10. 10School of Medicine, University of Western Australia, Western Australia, Perth, Australia
  11. 11Department of Rheumatology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
  12. 12Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway
  13. 13Department of Immunology, Oslo University Hospital, Oslo, Norway
  14. 14Department of Rheumatology, University Hospital Oslo, Oslo, Norway
  15. 15Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.
  16. 16Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
  17. 17King Abdulaziz University, Jeddah, Saudi Arabia
  18. 18Department of Medicine, Päijät-Häme Central Hospital, Lahti, Finland
  19. 19Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China
  20. 20Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
  21. 21VIB Inflammation Research Center, Ghent, Belgium
  22. 22Department of Rheumatology, Faculty of Medicine, Hospital General de México, Universidad Nacional Autónoma de México, Mexico City, México
  23. 23University of California, San Francisco, California, USA
  24. 24Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
  25. 25Division of Rheumatology, Toronto Western Hospital, Toronto, Ontario, Canada
  26. 26Rheumatology Department, Hospital Puerta de Hierro, Madrid, Spain
  27. 27Rheumatology Department, Complejo Hospitalario La Coruña, Instituto de Investigación Biomédica A Coruña (INIBIC), La Coruña, Spain
  28. 28Rheumatology Department, Hospital Marqués de Valcecilla, Instituto de Formación e Investigación Marqués de Valcecillas (IFIMAV), Santander, Spain
  29. 29Department of Immunology, Asturias Central University Hospital, Oviedo, Spain
  30. 30Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain
  31. 31National Institute for Health Research (NIHR) Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Oxford, UK
  32. 32Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, UK
  33. 33Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
  34. 34Division of Rheumatology, University of Toronto, Toronto, Ontario, Canada
  35. 35Toronto Western Research Institute, Toronto, Ontario, Canada
  36. 36Psoriatic Arthritis Program, University Health Network, Toronto, Ontario, Canada
  37. 37Memorial University of Newfoundland, St. John's, Newfoundland, Canada
  38. 38Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
  39. 39Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  40. 40Department of Medicine, Division of Allergy, Immunology, Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan.
  41. 41School of Medicine, National Yang- Ming University, Taipei, Taiwan
  42. 42SpA Group Hospital Militar, Universidad Militar Nueva Granada, Bogotá, Colombia
  43. 43Helgelandssykehuset, Mo i Rana, Norway
  44. 44Chronic Diseases Research Centre (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
  45. 45Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain
  46. 46Division of Rheumatology, Ambroise Paré Hospital, Assistance Publique–Hôpitaux de Paris, Boulogne-Billancourt, Paris, France
  47. 47MRC Integrative Epidemiology Unit, University of Bristol, UK
  48. 48School of Social and Community Medicine, University of Bristol, Bristol, UK
  49. 49National Institute for Health Research (NIHR) Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Oxford, UK
  1. Correspondence to Dr Matthew Brown, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Woolloongabba, Brisbane QLD 4102, Australia; matt.brown{at}uq.edu.au

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The association of endoplasmic reticulum aminopeptidase 2 (ERAP2) with ankylosing spondylitis (AS) was recently described in the large International Genetics of AS Consortium Immunochip study.1 Variants in ERAP2 have also been associated with inflammatory bowel disease, psoriasis, acute anterior uveitis and birdshot chorioretinopathy.2–5 Subsequent investigation demonstrated an association of ERAP2 with AS which was present when one conditioned on one of the two independent haplotypes of ERAP1 associated with AS or when HLA-B27-negative patients were analysed separately.1 These two analyses provide analogous evidence for the association of ERAP2 with AS in HLA-B27-negative cases because of the genetic interaction between HLA-B27 and the AS-associated ERAP1 variants in AS cases. ERAP1 and ERAP2 are located on chromosome 5q15 in the opposite orientation. The locus is challenging to analyse because of the strong linkage disequilibrium (LD) across the locus and the epistasis between ERAP1 and HLA-B alleles associated with AS. We therefore sought to investigate the association of ERAP2 with AS in HLA-B27-positive patients.6 This is of clinical importance because functional studies have demonstrated that the strongly AS-protective variant rs2248374 causes a functional ERAP2 protein knockout, because its G allele causes a loss of ERAP2 protein expression.5 ,7 There is also a variant of ERAP2 which changes its enzyme catalytic activity and specificity (rs2549782, K392A8). Because this is in almost complete LD with rs2248374 (1000 Genomes D′=1.00, r2=0.90), it is almost never translated in vivo. Further, the very strong LD between these markers means that analysis of rs2549782 for association would yield results almost identical to the results for rs2248374 presented below. Therefore, it is of relevance to determine whether the association of ERAP2 with HLA-B27-negative disease is also found in HLA-B27-positive cases, since ERAP inhibition may offer a novel therapeutic for AS.9

We studied European Immunochip HLA-B27-positive patients (n=7772), HLA-B*27-positive controls (n=1204) and unselected European controls (n=13,578). HLA-B*27-positive status was taken as an imputed allele dosage of 0.6 or greater in the HLA-B*27 tag SNP rs116488202 that has 99% sensitivity and 99% specificity for HLA-B*27 in Europeans.1 We used rs2248374 as a marker of the associated ERAP2 haplotype.

We then constructed a range of logistic regression models that controlled for ERAP1 haplotype association and included HLA-B27 controls and unselected controls and also included the first four eigenvectors to control for any potential population stratification. Analyses including only HLA-B27-positive controls are somewhat underpowered relative to the unselected control cohort but were included for illustrative purposes. Analyses were performed using R and the glm() function.

The results show that when using only HLA-B*27-positive patients with AS and either HLA-B*27-positive or unselected controls there is significant association at the ERAP2 locus (6.03×10−4 and 3.54×10−9 respectively; table 1 and figure 1). We also present the models excluding the two associated ERAP1 haplotypes to demonstrate that the nearby influence of these associations masks the underlying ERAP2 association.

Table 1

Logistic regression models of ERAP2 (rs2248374) association controlling for the AS-associated ERAP1 haplotypes (tagged by rs30187 and rs10050860) in HLA-B27-positive cases and either HLA-B27-positive or unselected controls

Figure 1

Local association plots of the ERAP2 locus when the association model using HLA-B27-positive controls (upper) and unselected controls (lower) are used in logistic regression models that incorporate the two independent ankylosing spondylitis-associated ERAP1 haplotypes, rs30187 and rs10050860, as covariates.

The significance of this finding is substantial. First, the conditional association noted in all patients with AS previously could have been solely the result of association in HLA-B*27-negative patients in the dataset.1 These data demonstrate that excluding HLA-B*27-negative patients still results in a robust level of association in logistic regression models that include only HLA-B*27-positive patients. The finding that ERAP2 is associated with protection from AS can now be unequivocally extended from HLA-B*27-negative patients with AS to all patients with AS, meaning potentially 8–9 times more patients could benefit from ERAP2 inhibition. Such aminopeptidase inhibitors are currently in development10 and have exciting therapeutic potential for AS and other immune-mediated diseases including inflammatory bowel disease, uveitis and psoriasis.

Acknowledgments

We wish to thank all the study participants who generously donated their DNA to the AS Immunochip study.

References

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Footnotes

  • Contributors PCR, MAB: conceived study; contributed patients/materials; contributed to or performed analysis. M-EC, PL, AC, DE: contributed to or performed analysis; wrote/reviewed/edited the paper. LAB, KH, SL, KBJ, S-CS, MW, MW, XZ, H-JG, GC, JN, BAL, ØF, JT, KL, LJ, YL, XW, DE, RB-V, LSG, SS, NH, JM, JLF-S, MAG-G, CL-L, PB, KG, JSHG, DDG, PR, WPM, HX, IEvdH-B, C-TC, RV-O, CR-S, IMH, FMP-S, RDI, JM, MB, JDR, T-HK, BPW: contributed patients/materials; wrote/reviewed/edited the paper.

  • Funding PR is funded by the RACP-ARA-Starr Research Fellowship. MAB is a National Health and Medical Research Council Senior Principle Research Fellow. This work was in part funded by grants from Arthritis Research UK (19536 & 18797), the NIHR Oxford Comprehensive Biomedical Research Centre (immunity and inflammation theme A93081), NIHR Thames Valley collaborative research network and National Ankylosing Spondylitis Society (UK) and NIH/NIAMS—P01-AR052915.

  • Competing interests None declared.

  • Ethics approval UQ Human Ethics and Metro South Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The data that the study uses have been fully detailed elsewhere.1

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