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

Publication ,  Journal Article
Rothwell, S; Chinoy, H; Lamb, JA; Miller, FW; Rider, LG; Wedderburn, LR; McHugh, NJ; Mammen, AL; Betteridge, ZE; Tansley, SL; Bowes, J ...
Published in: Ann Rheum Dis
July 2019

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<2.9×10-5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10-53 and HLA-DRB1*03:01, p=3.25×10-9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10-26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10-11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10-13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10-6). 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=3.47×10-64) and position 9 of HLA-B (p=7.03×10-11). 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.

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Published In

Ann Rheum Dis

DOI

EISSN

1468-2060

Publication Date

July 2019

Volume

78

Issue

7

Start / End Page

996 / 1002

Location

England

Related Subject Headings

  • White People
  • Polymorphism, Genetic
  • Myositis
  • Middle Aged
  • Male
  • Major Histocompatibility Complex
  • Humans
  • Haplotypes
  • HLA-DRB1 Chains
  • Genotype
 

Citation

APA
Chicago
ICMJE
MLA
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Rothwell, S., Chinoy, H., Lamb, J. A., Miller, F. W., Rider, L. G., Wedderburn, L. R., … Myositis Genetics Consortium (MYOGEN), . (2019). Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. Ann Rheum Dis, 78(7), 996–1002. https://doi.org/10.1136/annrheumdis-2019-215046
Rothwell, Simon, Hector Chinoy, Janine A. Lamb, Frederick W. Miller, Lisa G. Rider, Lucy R. Wedderburn, Neil J. McHugh, et al. “Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups.Ann Rheum Dis 78, no. 7 (July 2019): 996–1002. https://doi.org/10.1136/annrheumdis-2019-215046.
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. Ann Rheum Dis. 2019 Jul;78(7):996–1002.
Rothwell, Simon, et al. “Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups.Ann Rheum Dis, vol. 78, no. 7, July 2019, pp. 996–1002. Pubmed, doi:10.1136/annrheumdis-2019-215046.
Rothwell S, Chinoy H, Lamb JA, Miller FW, Rider LG, Wedderburn LR, McHugh NJ, Mammen AL, Betteridge ZE, Tansley SL, Bowes J, Vencovský J, Deakin CT, Dankó K, Vidya L, Selva-O’Callaghan A, Pachman LM, Reed AM, Molberg Ø, Benveniste O, Mathiesen PR, Radstake TRDJ, Doria A, de Bleecker J, Lee AT, Hanna MG, Machado PM, Ollier WE, Gregersen PK, Padyukov L, O’Hanlon TP, Cooper RG, Lundberg IE, Myositis Genetics Consortium (MYOGEN). Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. Ann Rheum Dis. 2019 Jul;78(7):996–1002.

Published In

Ann Rheum Dis

DOI

EISSN

1468-2060

Publication Date

July 2019

Volume

78

Issue

7

Start / End Page

996 / 1002

Location

England

Related Subject Headings

  • White People
  • Polymorphism, Genetic
  • Myositis
  • Middle Aged
  • Male
  • Major Histocompatibility Complex
  • Humans
  • Haplotypes
  • HLA-DRB1 Chains
  • Genotype