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

Simon Rothwell; 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; Ji I. Vencovský; Claire T. Deakin; Katalin Dankó; Limaye Vidya; Albert Selva-O'Callaghan; Lauren M. Pachman; Ann M. Reed; Yvind Molberg; Olivier Benveniste; Pernille R. Mathiesen; Timothy R.D.J. 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; Ingrid E. Lundberg

doi:10.1136/annrheumdis-2019-215046

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

Simon Rothwell^*, 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, Ji I. Vencovský, Claire T. Deakin, Katalin Dankó, Limaye Vidya, Albert Selva-O'Callaghan, Lauren M. Pachman, Ann M. Reed, Yvind Molberg, Olivier BenvenistePernille R. Mathiesen, Timothy R.D.J. 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, Ingrid E. Lundberg

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English (US)
Pages (from-to)	996-1002
Number of pages	7
Journal	Annals of the rheumatic diseases
Volume	78
Issue number	7
DOIs	https://doi.org/10.1136/annrheumdis-2019-215046
State	Published - Jul 1 2019

Keywords

HLA
autoantibody
genetics
idiopathic inflammatory myopathy
myositis

ASJC Scopus subject areas

Rheumatology
Immunology and Allergy
Immunology
General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/annrheumdis-2019-215046

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Rothwell, S., Chinoy, H., Lamb, J. A., Miller, F. W., Rider, L. G., Wedderburn, L. R., McHugh, N. J., Mammen, A. L., Betteridge, Z. E., Tansley, S. L., Bowes, J., Vencovský, J. I., Deakin, C. T., Dankó, K., Vidya, L., Selva-O'Callaghan, A., Pachman, L. M., Reed, A. M., Molberg, Y., ... Lundberg, I. E. (2019). Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. Annals of the rheumatic diseases, 78(7), 996-1002. https://doi.org/10.1136/annrheumdis-2019-215046

@article{8867f7611fbb438e867c68a2fe91d173,

title = "Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups",

abstract = "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.",

keywords = "HLA, autoantibody, genetics, idiopathic inflammatory myopathy, myositis",

author = "Simon Rothwell and Hector Chinoy 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 John Bowes and Vencovsk{\'y}, {Ji I.} and Deakin, {Claire T.} and Katalin Dank{\'o} and Limaye Vidya and Albert Selva-O'Callaghan and Pachman, {Lauren M.} and Reed, {Ann M.} and Yvind Molberg and Olivier Benveniste and Mathiesen, {Pernille R.} and Radstake, {Timothy R.D.J.} and Andrea Doria 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 Leonid Padyukov and O'Hanlon, {Terrance P.} and Cooper, {Robert G.} and Lundberg, {Ingrid E.}",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2019",

month = jul,

day = "1",

doi = "10.1136/annrheumdis-2019-215046",

language = "English (US)",

volume = "78",

pages = "996--1002",

journal = "Annals of the rheumatic diseases",

issn = "0003-4967",

publisher = "BMJ Publishing Group",

number = "7",

}

Rothwell, S, Chinoy, H, Lamb, JA, Miller, FW, Rider, LG, Wedderburn, LR, McHugh, NJ, Mammen, AL, Betteridge, ZE, Tansley, SL, Bowes, J, Vencovský, JI, Deakin, CT, Dankó, K, Vidya, L, Selva-O'Callaghan, A, Pachman, LM, Reed, AM, Molberg, Y, 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 2019, '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. https://doi.org/10.1136/annrheumdis-2019-215046

TY - JOUR

T1 - Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

AU - Rothwell, Simon

AU - Chinoy, Hector

AU - Lamb, Janine A.

AU - Miller, Frederick W.

AU - Rider, Lisa G.

AU - Wedderburn, Lucy R.

AU - McHugh, Neil J.

AU - Mammen, Andrew L.

AU - Betteridge, Zoe E.

AU - Tansley, Sarah L.

AU - Bowes, John

AU - Vencovský, Ji I.

AU - Deakin, Claire T.

AU - Dankó, Katalin

AU - Vidya, Limaye

AU - Selva-O'Callaghan, Albert

AU - Pachman, Lauren M.

AU - Reed, Ann M.

AU - Molberg, Yvind

AU - Benveniste, Olivier

AU - Mathiesen, Pernille R.

AU - Radstake, Timothy R.D.J.

AU - Doria, Andrea

AU - De Bleecker, Jan

AU - Lee, Annette T.

AU - Hanna, Michael G.

AU - Machado, Pedro M.

AU - Ollier, William E.

AU - Gregersen, Peter K.

AU - Padyukov, Leonid

AU - O'Hanlon, Terrance P.

AU - Cooper, Robert G.

AU - Lundberg, Ingrid E.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

KW - HLA

KW - autoantibody

KW - genetics

KW - idiopathic inflammatory myopathy

KW - myositis

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UR - http://www.scopus.com/inward/citedby.url?scp=85067232111&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2019-215046

DO - 10.1136/annrheumdis-2019-215046

M3 - Article

C2 - 31138531

AN - SCOPUS:85067232111

SN - 0003-4967

VL - 78

SP - 996

EP - 1002

JO - Annals of the rheumatic diseases

JF - Annals of the rheumatic diseases

IS - 7

ER -

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

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