Journal Article

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

Rautanen, Anna, Lopez-Larrea, Carlos, Bramon, Elvira, Plomin, Robert, Jankowski, Janusz, Kochan, Grazyna, Pirinen, Matti, Jiang, Lei, Trembath, Richard C, Danoy, Patrick, McCann, Owen T, Band, Gavin, Samani, Nilesh, McCarthy, Mark I, Markus, Hugh S, Bradbury, Linda A, Hunt, Sarah E, Appleton, Louise, Couto, Ana-Rita, Palmer, Colin N A, Bowness, Paul, Oppermann, Udo, Weisman, Michael H, Liu, Yu, Ferreira, Manuel A, Blackburn, Hannah, Deloukas, Panos, Donnelly, Peter, Wordsworth, Tom, Ward, Michael M, Sorrentino, Rosa, Ravindrarajah, Radhi, Marzo-Ortega, Helena, Rahman, Proton, Pointon, Jennifer J, Mathew, Christopher G, Sawcer, Stephen J, Bruges-Armas, Jacome, Inman, Robert D, Edkins, Sarah, Waller, Matthew, Karaderi, Tugce, Craddock, Nicholas, Gillman, Matthew, Liddle, Jennifer, Reveille, John D, Peltonen, Leena, Whittaker, Pamela, Duncanson, Audrey, Evans, David M, López-Vázquez, Antonio, Hammond, Naomi, Maksymowych, Walter, Widaa, Sara, Wood, Nicholas W, Dilthey, Alexander, Morgan, Ann, Viswanathan, Ananth C, Strange, Amy, Gladman, Dafna, Díaz-Peña, Roberto, Su, Zhan, Thomas, Gethin P, Harvey, David, Zayats,

2011

Overview

Matthew Brown, Peter Donnelly and colleagues report results of a genome-wide association meta-analysis and follow-up study of ankylosing spondylitis. They identify three new risk variants and report a genetic interaction between ERAP1 and HLA-B27, implicating aberrant peptide handling in the pathophysiology of this disease. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/727/2000 / 631/250/21/324/1509 / 692/699/1670/2766/1827 / Agriculture / Aminopeptidases - genetics / Aminopeptidases - metabolism / Animal Genetics and Genomics / Ankylosing spondylitis / Biological and medical sciences / Biomedical and Life Sciences / Biomedical research / Biomedicine / Cancer Research / CARD Signaling Adaptor Proteins - genetics / Case-Control Studies / CD8-Positive T-Lymphocytes - metabolism / Core Binding Factor Alpha 3 Subunit - genetics / Deoxyribonucleic acid / Disease Susceptibility / Diseases of the osteoarticular system / Diseases of the spine / DNA / Fundamental and applied biological sciences. Psychology / Gene expression / Gene Function / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Genome-Wide Association Study / Genomes / Histocompatibility antigens / HLA histocompatibility antigens / HLA-B27 Antigen - genetics / Human Genetics / Humans / Immunotherapy / Inflammatory bowel disease / Inflammatory joint diseases / Interleukin-12 Subunit p40 - genetics / Latent TGF-beta Binding Proteins - genetics / Lymphocytes / Medical research / Medical sciences / Membrane Proteins - genetics / Meta-Analysis as Topic / Minor Histocompatibility Antigens / Peptide Fragments - metabolism / Peptides / Physiological aspects / Polymorphism, Genetic - genetics / Quality control / Receptors, Peptide / Receptors, Prostaglandin E, EP4 Subtype - genetics / Receptors, Tumor Necrosis Factor, Type I - genetics / Risk factors / Single nucleotide polymorphisms / Spine / Spondylitis, Ankylosing - genetics / Spondylitis, Ankylosing - metabolism / White People