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.

Beth Israel Deaconess Medical Center Boston Massachusetts and Radboud University Nijmegen Nijmegen The Netherlands

Central Manchester University Hospitals NHS Foundation Trust University of Manchester Manchester UK

Charles University Prague Czech Republic

Dartmouth College Hanover New Hampshire

Feinstein Institute for Medical Research Manhasset New York

Ghent University Hospital Ghent Belgium

Helmholtz Zentrum München Neuherberg Germany

Hôpital Pitié Salpêtrière UPMC Paris France

Karolinska Institutet Stockholm Sweden

Karolinska University Hospital Karolinska Institutet Stockholm Sweden

Radboud University Nijmegen Nijmegen The Netherlands

Royal Adelaide Hospital Adelaide South Australia Australia

Salford Royal NHS Foundation Trust Salford UK

Technische Universität München Munich Germany and Helmholtz Zentrum München Neuherberg Germany

University College London London UK

University Medical Center Utrecht Utrecht The Netherlands

University of California Davis

University of Debrecen Debrecen Hungary

University of Liverpool Liverpool UK

University of Manchester Manchester UK

University of Manchester Manchester UK and Salford Royal NHS Foundation Trust Salford UK

University of Oslo Oslo Norway

University of Padova Padua Italy

Vall d'Hebron General Hospital Barcelona Spain

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Nat Rev Rheumatol. 2017 Mar;13(3):131. doi: 10.1038/nrrheum.2017.8. PubMed

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Discovery of new myositis genetic associations through leveraging other immune-mediated diseases

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

Idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups