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

Myositis Genetics Consortium (MYOGEN)

Research output: Contribution to journalArticle

1 Citation (Scopus)

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<2.9×10-5. 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 languageEnglish
Pages (from-to)996-1002
Number of pages7
JournalAnnals of the Rheumatic Diseases
Volume78
Issue number7
Early online date28 May 2019
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • HLA
  • autoantibody
  • genetics
  • idiopathic inflammatory myopathy
  • myositis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. / Myositis Genetics Consortium (MYOGEN).

In: Annals of the Rheumatic Diseases, Vol. 78, No. 7, 01.07.2019, p. 996-1002.

Research output: Contribution to journalArticle

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title = "Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups",
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<2.9×10-5. 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 = "{Myositis Genetics Consortium (MYOGEN)} and 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 Jiř{\'i} Vencovsk{\'y} 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 {\O}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 = "{\circledC} 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.",
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TY - JOUR

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

AU - Myositis Genetics Consortium (MYOGEN)

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, Jiří

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, Øyvind

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

N1 - © 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.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

KW - HLA

KW - autoantibody

KW - genetics

KW - idiopathic inflammatory myopathy

KW - myositis

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U2 - 10.1136/annrheumdis-2019-215046

DO - 10.1136/annrheumdis-2019-215046

M3 - Article

VL - 78

SP - 996

EP - 1002

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 7

ER -