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Immune-array analysis in sporadic inclusion body myositis reveals HLA-DRB1 amino acid heterogeneity across the myositis spectrum

(2017) ARTHRITIS & RHEUMATOLOGY. 69(5). p.1090-1099
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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 IBMis 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 x 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 50-nucleotidase 1A-positive status was found independent ofHLA-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.
Keywords
IDIOPATHIC INFLAMMATORY MYOPATHIES, CYTOSOLIC 5'-NUCLEOTIDASE 1A, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, RHEUMATOID-ARTHRITIS, MULTIPLE COMMON, CELIAC-DISEASE, ALLELES, VARIANTS, GENE

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Citation

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Chicago
Rothwell, Simon, Robert G Cooper, Ingrid E Lundberg, Peter K Gregersen, Michael G Hanna, Pedro M Machado, Megan K Herbert, et al. 2017. “Immune-array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum.” Arthritis & Rheumatology 69 (5): 1090–1099.
APA
Rothwell, S., Cooper, R. G., Lundberg, I. E., Gregersen, P. K., Hanna, M. G., Machado, P. M., Herbert, M. K., et al. (2017). Immune-array analysis in sporadic inclusion body myositis reveals HLA-DRB1 amino acid heterogeneity across the myositis spectrum. ARTHRITIS & RHEUMATOLOGY, 69(5), 1090–1099.
Vancouver
1.
Rothwell S, Cooper RG, Lundberg IE, Gregersen PK, Hanna MG, Machado PM, et al. Immune-array analysis in sporadic inclusion body myositis reveals HLA-DRB1 amino acid heterogeneity across the myositis spectrum. ARTHRITIS & RHEUMATOLOGY. 2017;69(5):1090–9.
MLA
Rothwell, Simon, Robert G Cooper, Ingrid E Lundberg, et al. “Immune-array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum.” ARTHRITIS & RHEUMATOLOGY 69.5 (2017): 1090–1099. Print.
@article{8507730,
  abstract     = {Objective. Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBMis 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 x 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 50-nucleotidase 1A-positive status was found independent ofHLA-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.},
  author       = {Rothwell, Simon and Cooper, Robert G and Lundberg, Ingrid E and Gregersen, Peter K and Hanna, Michael G and Machado, Pedro M and Herbert, Megan K and Pruijn, Ger JM and Lilleker, James B and Roberts, Mark and Bowes, John and Seldin, Michael F and Vencovsky, Jiri and Danko, Katalin and Limaye, Vidya and Selva-O'Callaghan, Albert and Platt, Hazel and Molberg, {\O}yvind and Benveniste, Olivier and Radstake, Timothy RDJ and Doria, Andrea and De Bleecker, Jan and De Paepe, Boel and Gieger, Christian and Meitinger, Thomas and Winkelmann, Juliane and Amos, Christopher I and Ollier, William E and Padyukov, Leonid and Lee, Annette T and Lamb, Janine A and Chinoy, Hector},
  issn         = {2326-5191},
  journal      = {ARTHRITIS \& RHEUMATOLOGY},
  language     = {eng},
  number       = {5},
  pages        = {1090--1099},
  title        = {Immune-array analysis in sporadic inclusion body myositis reveals HLA-DRB1 amino acid heterogeneity across the myositis spectrum},
  url          = {http://dx.doi.org/10.1002/art.40045},
  volume       = {69},
  year         = {2017},
}

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