Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

for the Myositis Genetics Consortium

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Objective: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is 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 × 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 5′-nucleotidase 1A–positive status was found independent of HLA–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.

Original languageEnglish (US)
Pages (from-to)1090-1099
Number of pages10
JournalArthritis and Rheumatology
Volume69
Issue number5
DOIs
StatePublished - May 1 2017

Fingerprint

Inclusion Body Myositis
Myositis
Amino Acids
Chromosomes, Human, Pair 3
Genetic Association Studies
5'-Nucleotidase
Peptides
Frameshift Mutation
Dermatomyositis
Disease Susceptibility
Age of Onset
Autoimmune Diseases
Alleles
Genotype
Muscles

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum. / for the Myositis Genetics Consortium.

In: Arthritis and Rheumatology, Vol. 69, No. 5, 01.05.2017, p. 1090-1099.

Research output: Contribution to journalArticle

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title = "Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum",
abstract = "Objective: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is 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 × 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 5′-nucleotidase 1A–positive status was found independent of HLA–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 = "{for the Myositis Genetics Consortium} and Simon Rothwell 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 J.M.} and Lilleker, {James B.} and Mark Roberts and John Bowes and Seldin, {Michael F} and Jiri Vencovsky and Katalin Danko and Vidya Limaye and Albert Selva-O'Callaghan and Hazel Platt and {\O}yvind Molberg and Olivier Benveniste and Radstake, {Timothy R.D.J.} and Andrea Doria and {De Bleecker}, Jan and {De Paepe}, Boel and Christian Gieger and Thomas Meitinger and Juliane Winkelmann and Amos, {Christopher I.} and Ollier, {William E.} and Leonid Padyukov and Lee, {Annette T.} and Lamb, {Janine A.} and Hector Chinoy and Christopher Denton and Karina Gheorghe and David Hilton-Jones and Patrick Kiely and Herman Mann",
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T1 - Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA–DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum

AU - for the Myositis Genetics Consortium

AU - Rothwell, Simon

AU - Cooper, Robert G.

AU - Lundberg, Ingrid E.

AU - Gregersen, Peter K.

AU - Hanna, Michael G.

AU - Machado, Pedro M.

AU - Herbert, Megan K.

AU - Pruijn, Ger J.M.

AU - Lilleker, James B.

AU - Roberts, Mark

AU - Bowes, John

AU - Seldin, Michael F

AU - Vencovsky, Jiri

AU - Danko, Katalin

AU - Limaye, Vidya

AU - Selva-O'Callaghan, Albert

AU - Platt, Hazel

AU - Molberg, Øyvind

AU - Benveniste, Olivier

AU - Radstake, Timothy R.D.J.

AU - Doria, Andrea

AU - De Bleecker, Jan

AU - De Paepe, Boel

AU - Gieger, Christian

AU - Meitinger, Thomas

AU - Winkelmann, Juliane

AU - Amos, Christopher I.

AU - Ollier, William E.

AU - Padyukov, Leonid

AU - Lee, Annette T.

AU - Lamb, Janine A.

AU - Chinoy, Hector

AU - Denton, Christopher

AU - Gheorghe, Karina

AU - Hilton-Jones, David

AU - Kiely, Patrick

AU - Mann, Herman

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N2 - Objective: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is 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 × 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 5′-nucleotidase 1A–positive status was found independent of HLA–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.

AB - Objective: Inclusion body myositis (IBM) is characterized by a combination of inflammatory and degenerative changes affecting muscle. While the primary cause of IBM is 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 × 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 5′-nucleotidase 1A–positive status was found independent of HLA–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.

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