Dataset Information

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

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.

SUBMITTER: Evans DM

PROVIDER: S-EPMC3640413 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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

Evans David M DM Spencer Chris C A CC Pointon Jennifer J JJ Su Zhan Z Harvey David D Kochan Grazyna G Oppermann Udo U Dilthey Alexander A Pirinen Matti M Stone Millicent A MA Appleton Louise L Moutsianas Loukas L Leslie Stephen S Wordsworth Tom T Kenna Tony J TJ Karaderi Tugce T Thomas Gethin P GP Ward Michael M MM Weisman Michael H MH Farrar Claire C Bradbury Linda A LA Danoy Patrick P Inman Robert D RD Maksymowych Walter W Gladman Dafna D Rahman Proton P Morgan Ann A Marzo-Ortega Helena H Bowness Paul P Gaffney Karl K Gaston J S Hill JS Smith Malcolm M Bruges-Armas Jacome J Couto Ana-Rita AR Sorrentino Rosa R Paladini Fabiana F Ferreira Manuel A MA Xu Huji H Liu Yu Y Jiang Lei L Lopez-Larrea Carlos C Díaz-Peña Roberto R López-Vázquez Antonio A Zayats Tetyana T Band Gavin G Bellenguez Céline C Blackburn Hannah H Blackwell Jenefer M JM Bramon Elvira E Bumpstead Suzannah J SJ Casas Juan P JP Corvin Aiden A Craddock Nicholas N Deloukas Panos P Dronov Serge S Duncanson Audrey A Edkins Sarah S Freeman Colin C Gillman Matthew M Gray Emma E Gwilliam Rhian R Hammond Naomi N Hunt Sarah E SE Jankowski Janusz J Jayakumar Alagurevathi A Langford Cordelia C Liddle Jennifer J Markus Hugh S HS Mathew Christopher G CG McCann Owen T OT McCarthy Mark I MI Palmer Colin N A CN Peltonen Leena L Plomin Robert R Potter Simon C SC Rautanen Anna A Ravindrarajah Radhi R Ricketts Michelle M Samani Nilesh N Sawcer Stephen J SJ Strange Amy A Trembath Richard C RC Viswanathan Ananth C AC Waller Matthew M Weston Paul P Whittaker Pamela P Widaa Sara S Wood Nicholas W NW McVean Gilean G Reveille John D JD Wordsworth B Paul BP Brown Matthew A MA Donnelly Peter P

Nature genetics 20110710 8

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 ...[more]

PMID: 21743469

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Project description:Ankylosing spondylitis (AS) is a familial, heritable disease specified by syndesmophyte formation leading to an ankylosed spine. Endoplasmic reticulum aminopeptidase 1 (ERAP1) genetic variations have been widely proved to be associated with AS in several ethnic populations. The aim of this study was to investigate whether ERAP1 single nucleotide polymorphisms (SNPs) are associated with AS susceptibility and disease severity in Taiwanese.Four ERAP1 SNPs (rs27037, rs27980, rs27044 and rs30187) were genotyped in 797 Taiwanese AS patients and 1,150 healthy controls. Distributions of genotype and alleles were compared between AS patients and healthy controls, and among AS patients stratified by clinical parameters.The SNP rs27037T allele appeared to be a risk factor for AS susceptibility (P = 5.5 × 10-5, OR 1.30, 95% CI: 1.15 to 1.48; GT+TT vs. GG P = 9.3 × 10-5, OR 1.49, 95% CI: 1.22 to 1.82). In addition, the coding SNP (cSNP) rs27044G allele (P = 1.5 × 10-4, OR 1.28, 95% CI: 1.13 to 1.46; CG+GG vs. CC, P = 1.7 × 10-3, OR 1.44, 95% CI: 1.15 to 1.81) and the cSNP rs30187T allele (P = 1.7 × 10-3, OR 1.23, 95% CI: 1.08 to 1.40; CT+TT vs. CC P = 6.1 × 10-3, OR 1.38, 95% CI: 1.10 to 1.74) were predisposing factors for AS. Notably, the rs27044G allele carriers (CG+GG vs. CC, P = 0.015, OR 1.59, 95% CI: 1.33 to 2.30) and rs30187T allele carriers (CT+TT vs. CC, P = 0.011, OR 1.63, 95% CI: 1.12 to 2.38) were susceptible to syndesmophyte formation in AS patients. Furthermore, two cSNPs (rs27044 and rs30187) strongly associated with HLA-B27 positivity in AS patients. Finally, the ERAP1 SNP haplotype TCG (rs27037T/rs27980C/rs27044G) is a major risk factor for AS (adjusted P <0.00001, OR 1.38, 95% CI: 1.12 to 1.58) in Taiwanese.This study provides the first evidence of ERAP1 SNPs involving syndesmophyte formation. The interactions between ERAP1 SNPs and HLA-B27 play critical roles in pMHC I pathway processing contributing to the pathogenesis of AS in multiple populations.

Dataset Information

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

Publications

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

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