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OBJECTIVE: Inclusion body myositis (IBM) is characterised by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is unknown, genetic factors may influence disease susceptibility. We conducted the largest genetic association study to date in IBM, investigating immune-related genes using the Immunochip.
METHODS: 252 Caucasian IBM cases were recruited from 11 countries through the Myositis Genetics Consortium (MYOGEN), and compared with 1,008 ethnically matched controls. Classical HLA alleles and amino acids were imputed using SNP2HLA.
RESULTS: HLA was confirmed as the most strongly associated region (p=3.58x10(-33) ) in IBM. HLA imputation identified three 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-cN-1A positive status was found independent of HLA-DRB1*03:01. There was no association of HLA genotypes with age of onset of IBM. Three non-HLA regions reached suggestive significance, including chr3(p21.21), an established risk locus for autoimmune disease, where a frameshift mutation in CCR5 is thought to be the causal variant.
INTERPRETATION: 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 auto-antigenic peptides. A novel suggestive association within the chr3(p21.21) locus suggests a role for CCR5. This article is protected by copyright. All rights reserved.
|Journal||Arthritis & Rheumatology (Hoboken)|
|Early online date||13 Jan 2017|
|Publication status||Published - 13 Jan 2017|
FingerprintDive into the research topics of 'Immune-array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity across the Myositis Spectrum'. Together they form a unique fingerprint.
MMRG: Manchester Myositis Research Group
Chinoy, H., Lamb, J., Ollier, W., Rothwell, S., Lilleker, J., Oldroyd, A., Snedden, A., Platt, H. & New, P.
1/01/10 → …
Arthritis Research UK Centre of Excellence in the Genetics of Rheumatic Diseases.
Worthington, J., Barton, A., Black, G., Crow, Y., Eyre, S., Raychaudhuri, S. & Thomson, W.
1/08/13 → 31/07/18
Inflammatory myopathies: Genetic associations with IBM
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