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

(2019) ANNALS OF THE RHEUMATIC DISEASES. 78(7). p.996-1002
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Organization
Abstract
Objectives: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. Methods: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. Results: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9x10(-5). Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28x10(-53) and HLA-DRB1*03:01, p=3.25x10(-9)), anti-PM/Scl (HLA-DQB1*02:01, p=1.47x10(-26)) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40x10(-11)). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92x10(-13)) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09x10(-6)). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47x10(-64)) and position 9 of HLA-B (p=7.03x10(-11)). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. Conclusions: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
Keywords
CANCER-ASSOCIATED DERMATOMYOSITIS, IDIOPATHIC INFLAMMATORY MYOPATHY, JUVENILE DERMATOMYOSITIS, CLINICAL PHENOTYPE, PROTECTIVE FACTORS, GENETIC RISK, ONSET, HLA-DRB1, HISTORY, ADULT

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MLA
Rothwell, Simon et al. “Focused HLA Analysis in Caucasians with Myositis Identifies Significant Associations with Autoantibody Subgroups.” ANNALS OF THE RHEUMATIC DISEASES 78.7 (2019): 996–1002. Print.
APA
Rothwell, Simon, Chinoy, H., Lamb, J. A., Miller, F. W., Rider, L. G., Wedderburn, L. R., McHugh, N. J., et al. (2019). Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. ANNALS OF THE RHEUMATIC DISEASES, 78(7), 996–1002.
Chicago author-date
Rothwell, Simon, Hector Chinoy, Janine A Lamb, Frederick W Miller, Lisa G Rider, Lucy R Wedderburn, Neil J McHugh, et al. 2019. “Focused HLA Analysis in Caucasians with Myositis Identifies Significant Associations with Autoantibody Subgroups.” Annals of the Rheumatic Diseases 78 (7): 996–1002.
Chicago author-date (all authors)
Rothwell, Simon, Hector Chinoy, Janine A Lamb, Frederick W Miller, Lisa G Rider, Lucy R Wedderburn, Neil J McHugh, Andrew L Mammen, Zoe E Betteridge, Sarah L Tansley, John Bowes, Jiri Vencovský, Claire T Deakin, Katalin Dankó, Limaye Vidya, Albert Selva-O’Callaghan, Lauren M Pachman, Ann M Reed, Øyvind Molberg, Oliver Benveniste, Pernille R Mathiesen, Timothy RDJ Radstake, Andrea Doria, Jan De Bleecker, Annette T Lee, Michael G Hanna, Pedro M Machado, William E Ollier, Peter K Gregersen, Leonid Padyukov, Terrance P O’Hanlon, Robert G Cooper, and Ingrid E Lundberg. 2019. “Focused HLA Analysis in Caucasians with Myositis Identifies Significant Associations with Autoantibody Subgroups.” Annals of the Rheumatic Diseases 78 (7): 996–1002.
Vancouver
1.
Rothwell S, Chinoy H, Lamb JA, Miller FW, Rider LG, Wedderburn LR, et al. Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. ANNALS OF THE RHEUMATIC DISEASES. 2019;78(7):996–1002.
IEEE
[1]
S. Rothwell et al., “Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups,” ANNALS OF THE RHEUMATIC DISEASES, vol. 78, no. 7, pp. 996–1002, 2019.
@article{8618334,
  abstract     = {Objectives: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. 
Methods: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. 
Results: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9x10(-5). Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28x10(-53) and HLA-DRB1*03:01, p=3.25x10(-9)), anti-PM/Scl (HLA-DQB1*02:01, p=1.47x10(-26)) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40x10(-11)). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92x10(-13)) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09x10(-6)). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47x10(-64)) and position 9 of HLA-B (p=7.03x10(-11)). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. 
Conclusions: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.},
  author       = {Rothwell, Simon and Chinoy, Hector and Lamb, Janine A and Miller, Frederick W and Rider, Lisa G and Wedderburn, Lucy R and McHugh, Neil J and Mammen, Andrew L and Betteridge, Zoe E and Tansley, Sarah L and Bowes, John and Vencovský, Jiri and Deakin, Claire T and Dankó, Katalin and Vidya, Limaye and Selva-O'Callaghan, Albert and Pachman, Lauren M and Reed, Ann M and Molberg, Øyvind and Benveniste, Oliver and Mathiesen, Pernille R and Radstake, Timothy RDJ and Doria, Andrea and De Bleecker, Jan and Lee, Annette T and Hanna, Michael G and Machado, Pedro M and Ollier, William E and Gregersen, Peter K and Padyukov, Leonid and O'Hanlon, Terrance P and Cooper, Robert G and Lundberg, Ingrid E},
  issn         = {0003-4967},
  journal      = {ANNALS OF THE RHEUMATIC DISEASES},
  keywords     = {CANCER-ASSOCIATED DERMATOMYOSITIS,IDIOPATHIC INFLAMMATORY MYOPATHY,JUVENILE DERMATOMYOSITIS,CLINICAL PHENOTYPE,PROTECTIVE FACTORS,GENETIC RISK,ONSET,HLA-DRB1,HISTORY,ADULT},
  language     = {eng},
  number       = {7},
  pages        = {996--1002},
  title        = {Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2019-215046},
  volume       = {78},
  year         = {2019},
}

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