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Arthritis Rheumatol. 2017 May;69(5):1090-1099. doi: 10.1002/art.40045. Epub 2017 Apr 4.

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

Author information

1
University of Manchester, Manchester, UK.
2
University of Liverpool, Liverpool, UK.
3
Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
4
Feinstein Institute for Medical Research, Manhasset, New York.
5
University College London, London, UK.
6
Beth Israel Deaconess Medical Center, Boston, Massachusetts, and Radboud University Nijmegen, Nijmegen, The Netherlands.
7
Radboud University Nijmegen, Nijmegen, The Netherlands.
8
University of Manchester, Manchester, UK, and Salford Royal NHS Foundation Trust, Salford, UK.
9
Salford Royal NHS Foundation Trust, Salford, UK.
10
University of California, Davis.
11
Charles University, Prague, Czech Republic.
12
University of Debrecen, Debrecen, Hungary.
13
Royal Adelaide Hospital, Adelaide, South Australia, Australia.
14
Vall d'Hebron General Hospital, Barcelona, Spain.
15
University of Oslo, Oslo, Norway.
16
Hôpital Pitié-Salpêtrière, UPMC, Paris, France.
17
University Medical Center Utrecht, Utrecht, The Netherlands.
18
University of Padova, Padua, Italy.
19
Ghent University Hospital, Ghent, Belgium.
20
Helmholtz Zentrum München, Neuherberg, Germany.
21
Technische Universität München, Munich, Germany, and Helmholtz Zentrum München, Neuherberg, Germany.
22
Dartmouth College, Hanover, New Hampshire.
23
Karolinska Institutet, Stockholm, Sweden.
24
Central Manchester University Hospitals NHS Foundation Trust, University of Manchester, Manchester, UK.

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.

PMID:
28086002
PMCID:
PMC5516174
DOI:
10.1002/art.40045
[Indexed for MEDLINE]
Free PMC Article

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