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Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

Rothwell, S; Cooper, RG; Lundberg, IE; Gregersen, PK; Hanna, MG; Machado, PM; Herbert, MK; ... Chinoy, H; + view all (2017) Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum. Arthritis & Rheumatology , 69 (5) pp. 1090-1099. 10.1002/art.40045. Green open access

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Abstract

OBJECTIVE: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. To determine genetic factors contributing to the etiology of IBM, we conducted the largest genetic association study of the disease to date, investigating immune-related genes using the Immunochip. METHODS: A total of 252 Caucasian patients with IBM were recruited from 11 countries through the Myositis Genetics Consortium and compared with 1,008 ethnically matched controls. Classic HLA alleles and amino acids were imputed using SNP2HLA. RESULTS: The HLA region was confirmed as the most strongly associated region in IBM (P = 3.58 × 10−33). HLA imputation identified 3 independent associations (with HLA–DRB1*03:01, DRB1*01:01, and DRB1*13:01), although the strongest association was with amino acid positions 26 and 11 of the HLA–DRB1 molecule. No association with anti–cytosolic 5′-nucleotidase 1A–positive status was found independent of HLA–DRB1*03:01. There was no association of HLA genotypes with age at onset of IBM. Three non-HLA regions reached suggestive significance, including the chromosome 3 p21.31 region, an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant. CONCLUSION: This is the largest, most comprehensive genetic association study to date in IBM. The data confirm that HLA is the most strongly associated region and identifies novel amino acid associations that may explain the risk in this locus. These amino acid associations differentiate IBM from polymyositis and dermatomyositis and may determine properties of the peptide-binding groove, allowing it to preferentially bind autoantigenic peptides. A novel suggestive association within the chromosome 3 p21.31 region suggests a role for CCR5.

Type: Article
Title: Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/art.40045
Publisher version: http://dx.doi.org/10.1002/art.40045
Language: English
Additional information: © 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc.on behalf of American College of Rheumatology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology, Life Sciences & Biomedicine, Rheumatology, Idiopathic Inflammatory Myopathies, Cytosolic 5'-Nucleotidase 1A, Genome-Wide Association, Susceptibility Loci, Rheumatoid-Arthritis, Multiple Common, Celiac-Disease, Alleles, Variants, Gene
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/1538432
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