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PMID: 21743469 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.

Nature genetics ·Vol. 43 ·No. 8 ·2011-07-10 ·Pages 761-7

Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, Oppermann U, Opperman U, Dilthey A, Pirinen M, Stone MA, Appleton L, Moutsianas L, Moutsianis L, Leslie S, Wordsworth T, Kenna TJ, Karaderi T, Thomas GP, Ward MM, Weisman MH, Farrar C, Bradbury LA, Danoy P, Inman RD, Maksymowych W, Gladman D, Rahman P, Spondyloarthritis Research Consortium of Canada SPARCC, Morgan A, Marzo-Ortega H, Bowness P, Gaffney K, Gaston JS, Smith M, Bruges-Armas J, Couto AR, Sorrentino R, Paladini F, Ferreira MA, Xu H, Liu Y, Jiang L, Lopez-Larrea C, Díaz-Peña R, López-Vázquez A, Zayats T, Band G, Bellenguez C, Blackburn H, Blackwell JM, Bramon E, Bumpstead SJ, Casas JP, Corvin A, Craddock N, Deloukas P, Dronov S, Duncanson A, Edkins S, Freeman C, Gillman M, Gray E, Gwilliam R, Hammond N, Hunt SE, Jankowski J, Jayakumar A, Langford C, Liddle J, Markus HS, Mathew CG, McCann OT, McCarthy MI, Palmer CN, Peltonen L, Plomin R, Potter SC, Rautanen A, Ravindrarajah R, Ricketts M, Samani N, Sawcer SJ, Strange A, Trembath RC, Viswanathan AC, Waller M, Weston P, Whittaker P, Widaa S, Wood NW, McVean G, Reveille JD, Wordsworth BP, Brown MA, Donnelly P, Australo-Anglo-American Spondyloarthritis Consortium TASC, Wellcome Trust Case Control Consortium 2 WTCCC2

Abstract

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

MeSH Terms
Aminopeptidases/genetics,metabolism CARD Signaling Adaptor Proteins/genetics CD8-Positive T-Lymphocytes/metabolism Case-Control Studies Core Binding Factor Alpha 3 Subunit/genetics Disease Susceptibility Genome-Wide Association Study HLA-B27 Antigen/genetics Humans Interleukin-12 Subunit p40/genetics Latent TGF-beta Binding Proteins/genetics Membrane Proteins/genetics Meta-Analysis as Topic Minor Histocompatibility Antigens Peptide Fragments/metabolism Polymorphism, Genetic/genetics Receptors, Peptide Receptors, Prostaglandin E, EP4 Subtype/genetics Receptors, Tumor Necrosis Factor, Type I/genetics Spondylitis, Ankylosing/genetics,metabolism Whites
Chemicals
ANTXR2 protein, human CARD Signaling Adaptor Proteins CARD9 protein, human Core Binding Factor Alpha 3 Subunit HLA-B27 Antigen IL12B protein, human Interleukin-12 Subunit p40 LTBP4 protein, human Latent TGF-beta Binding Proteins Membrane Proteins Minor Histocompatibility Antigens PTGER4 protein, human Peptide Fragments Receptors, Peptide Receptors, Prostaglandin E, EP4 Subtype Receptors, Tumor Necrosis Factor, Type I Runx3 protein, human TNFRSF1A protein, human Aminopeptidases ERAP1 protein, human
Authors & Affiliations
98 authors, click to expand affiliations / ORCID
Evans David M
Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Spencer Chris C A
Pointon Jennifer J
Su Zhan
Harvey David
Kochan Grazyna
Oppermann Udo
Opperman Udo
Dilthey Alexander
Pirinen Matti
Stone Millicent A
Appleton Louise
Moutsianas Loukas
Moutsianis Loukas
Leslie Stephen
Wordsworth Tom
Kenna Tony J
Karaderi Tugce
Thomas Gethin P
Ward Michael M
Weisman Michael H
Farrar Claire
Bradbury Linda A
Danoy Patrick
Inman Robert D
Maksymowych Walter
Gladman Dafna
Rahman Proton
Spondyloarthritis Research Consortium of Canada (SPARCC)
Morgan Ann
Marzo-Ortega Helena
Bowness Paul
Gaffney Karl
Gaston J S Hill
Smith Malcolm
Bruges-Armas Jacome
Couto Ana-Rita
Sorrentino Rosa
Paladini Fabiana
Ferreira Manuel A
Xu Huji
Liu Yu
Jiang Lei
Lopez-Larrea Carlos
Díaz-Peña Roberto
López-Vázquez Antonio
Zayats Tetyana
Band Gavin
Bellenguez Céline
Blackburn Hannah
Blackwell Jenefer M
Bramon Elvira
Bumpstead Suzannah J
Casas Juan P
Corvin Aiden
Craddock Nicholas
Deloukas Panos
Dronov Serge
Duncanson Audrey
Edkins Sarah
Freeman Colin
Gillman Matthew
Gray Emma
Gwilliam Rhian
Hammond Naomi
Hunt Sarah E
Jankowski Janusz
Jayakumar Alagurevathi
Langford Cordelia
Liddle Jennifer
Markus Hugh S
Mathew Christopher G
McCann Owen T
McCarthy Mark I
Palmer Colin N A
Peltonen Leena
Plomin Robert
Potter Simon C
Rautanen Anna
Ravindrarajah Radhi
Ricketts Michelle
Samani Nilesh
Sawcer Stephen J
Strange Amy
Trembath Richard C
Viswanathan Ananth C
Waller Matthew
Weston Paul
Whittaker Pamela
Widaa Sara
Wood Nicholas W
McVean Gilean
Reveille John D
Wordsworth B Paul
Brown Matthew A
Donnelly Peter
Australo-Anglo-American Spondyloarthritis Consortium (TASC)
Wellcome Trust Case Control Consortium 2 (WTCCC2)
References (47)
47 references, click to expand
  1. Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
    Nat Genet. 2009 Feb;41(2):205-10 PMID: 19169255
  2. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom.
    Ann Rheum Dis. 1996 Apr;55(4):268-70 PMID: 8733445
  3. A genotype calling algorithm for the Illumina BeadArray platform.
    Bioinformatics. 2007 Oct 15;23(20):2741-6 PMID: 17846035
  4. Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding.
    J Clin Invest. 2002 Aug;110(4):515-26 PMID: 12189246
  5. Endogenous PGE2 promotes the induction of human Th17 responses by fungal ß-glucan.
    J Leukoc Biol. 2010 Nov;88(5):947-54 PMID: 20807707
  6. HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Evidence for new associations.
    Tissue Antigens. 1995 Mar;45(3):169-76 PMID: 7761976
  7. An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides.
    Nat Immunol. 2002 Dec;3(12):1169-76 PMID: 12436109
  8. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis.
    Arthritis Rheum. 2009 Jun;60(6):1647-56 PMID: 19479869
  9. Linkage strategies for genetically complex traits. I. Multilocus models.
    Am J Hum Genet. 1990 Feb;46(2):222-8 PMID: 2301392
  10. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci.
    Nat Genet. 2010 Feb;42(2):123-7 PMID: 20062062
  11. Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis.
    J Rheumatol. 2009 Apr;36(4):801-8 PMID: 19273449
  12. Ankylosing spondylitis in Danish and Norwegian twins: occurrence and the relative importance of genetic vs. environmental effectors in disease causation.
    Scand J Rheumatol. 2008 Mar-Apr;37(2):120-6 PMID: 18415769
  13. Origins and functional impact of copy number variation in the human genome.
    Nature. 2010 Apr 1;464(7289):704-12 PMID: 19812545
  14. Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21.
    Hum Mol Genet. 2011 Jan 15;20(2):345-53 PMID: 21044948
  15. Triplet repeat polymorphism in the MICA gene in HLA-B27 positive and negative caucasian patients with ankylosing spondylitis.
    Hum Immunol. 1999 Jan;60(1):83-6 PMID: 9952031
  16. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.
    Nat Genet. 2007 Nov;39(11):1329-37 PMID: 17952073
  17. Bayesian statistical methods for genetic association studies.
    Nat Rev Genet. 2009 Oct;10(10):681-90 PMID: 19763151
  18. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment.
    Arthritis Rheum. 1997 Oct;40(10):1823-8 PMID: 9336417
  19. A continuous fluorigenic assay for the measurement of the activity of endoplasmic reticulum aminopeptidase 1: competition kinetics as a tool for enzyme specificity investigation.
    Anal Biochem. 2009 Dec 1;395(1):33-40 PMID: 19638272
  20. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis.
    J Exp Med. 2007 Jan 22;204(1):41-7 PMID: 17227914
  21. Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis.
    Ann Rheum Dis. 2006 Jun;65(6):775-80 PMID: 16249228
  22. Elucidating the chromosome 9 association with AS; CARD9 is a candidate gene.
    Genes Immun. 2010 Sep;11(6):490-6 PMID: 20463747
  23. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study.
    Br J Rheumatol. 1983 Nov;22(4 Suppl 2):18-9 PMID: 6606472
  24. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies.
    PLoS Genet. 2009 Jun;5(6):e1000529 PMID: 19543373
  25. Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease.
    PLoS Genet. 2010 Dec 02;6(12):e1001195 PMID: 21152001
  26. Genotype imputation.
    Annu Rev Genomics Hum Genet. 2009;10:387-406 PMID: 19715440
  27. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
    Nat Genet. 2010 Nov;42(11):985-90 PMID: 20953190
  28. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
    Am J Hum Genet. 2007 Feb;80(2):273-90 PMID: 17236132
  29. The genetics and immunopathogenesis of inflammatory bowel disease.
    Nat Rev Immunol. 2008 Jun;8(6):458-66 PMID: 18500230
  30. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a "molecular ruler" mechanism.
    Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17107-12 PMID: 16286653
  31. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria.
    Arthritis Rheum. 1984 Apr;27(4):361-8 PMID: 6231933
  32. Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control.
    Am J Hum Genet. 2010 Jan;86(1):88-92 PMID: 20045101
  33. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis.
    Ann Rheum Dis. 2000 Nov;59(11):883-6 PMID: 11053066
  34. Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells.
    Nat Immunol. 2010 Mar;11(3):257-64 PMID: 20118929
  35. Analysis of gene expression data using BRB-ArrayTools.
    Cancer Inform. 2007 Feb 04;3:11-7 PMID: 19455231
  36. Assessing the role of HLA-linked and unlinked determinants of disease.
    Am J Hum Genet. 1987 Jan;40(1):1-14 PMID: 3468804
  37. PLINK: a tool set for whole-genome association and population-based linkage analyses.
    Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
  38. Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls.
    Arthritis Rheum. 1983 Dec;26(12):1460-4 PMID: 6606431
  39. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases.
    J Exp Med. 2008 Feb 18;205(2):331-7 PMID: 18250193
  40. Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis.
    Eur J Immunol. 1995 Nov;25(11):3199-201 PMID: 7489765
  41. An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding.
    J Biol Chem. 2003 Aug 1;278(31):28677-85 PMID: 12748171
  42. Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding.
    J Immunol. 2003 Dec 15;171(12):6814-9 PMID: 14662887
  43. Early-onset ankylosing spondylitis is associated with a functional MICA polymorphism.
    Hum Immunol. 2005 Oct;66(10):1057-61 PMID: 16386647
  44. lumi: a pipeline for processing Illumina microarray.
    Bioinformatics. 2008 Jul 1;24(13):1547-8 PMID: 18467348
  45. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
    Science. 2006 Dec 1;314(5804):1461-3 PMID: 17068223
  46. Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4.
    PLoS Genet. 2007 Apr 20;3(4):e58 PMID: 17447842
  47. The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD).
    Ann Rheum Dis. 2010 Jun;69(6):1243-6 PMID: 19854717
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.873
Published
2011-07-10
Epub
2011-00-10
Pages
761-7
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3640413
Subset
IM
Grants
Medical Research Council · G0600705 · United Kingdom
CIHR · Canada
NCRR NIH HHS · UL1RR024188 · United States
Wellcome Trust · 076113 · United Kingdom
NIAMS NIH HHS · R01 AR046208 · United States
Medical Research Council · G19/2 · United Kingdom
Wellcome Trust · 092809 · United Kingdom
NCRR NIH HHS · M01 RR000425 · United States
Medical Research Council · G0000934 · United Kingdom
Medical Research Council · G0901310 · United Kingdom
NCRR NIH HHS · MO1-RR00425 · United States
Intramural NIH HHS · ZIA AR041153-07 · United States
Department of Health · PDA/02/06/016 · United Kingdom
Medical Research Council · G0800582 · United Kingdom
Wellcome Trust · 083948/Z/07/Z · United Kingdom
NIAMS NIH HHS · R01-AR046208 · United States
Wellcome Trust · 068545/Z/02 · United Kingdom
Wellcome Trust · 090532 · United Kingdom
Arthritis Research UK · 19536 · United Kingdom
Arthritis Research UK · 18797 · United Kingdom
PHS HHS · P01-052915 · United States
Corrections
ErratumIn
-
CommentIn
PMID: 21808290
External Links
PubMed source DOI: 10.1038/ng.873 PMC Full Text View journal details
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