title: Immune-Array Analysis in Sporadic Inclusion Body Myositis Reveals HLA-DRB1 Amino Acid Heterogeneity Across the Myositis Spectrum.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Rothwell
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Cooper
authors.affiliation: Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: University College London, London, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: University College London, London, UK.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Machado
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, and Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Herbert
authors.affiliation: Radboud University Nijmegen, Nijmegen, The Netherlands.
authors.forename: Ger J M
authors.initials: GJM
authors.lastname: Pruijn
authors.affiliation: University of Manchester, Manchester, UK, and Salford Royal NHS Foundation Trust, Salford, UK.
authors.forename: James B
authors.initials: JB
authors.lastname: Lilleker
authors.affiliation: Salford Royal NHS Foundation Trust, Salford, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Roberts
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: John
authors.initials: J
authors.lastname: Bowes
authors.affiliation: University of California, Davis.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.affiliation: Charles University, Prague, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Vencovsky
authors.affiliation: University of Debrecen, Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Danko
authors.affiliation: Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Vidya
authors.initials: V
authors.lastname: Limaye
authors.affiliation: Vall d'Hebron General Hospital, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Selva-O'Callaghan
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Platt
authors.affiliation: University of Oslo, Oslo, Norway.
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Molberg
authors.affiliation: Hôpital Pitié-Salpêtrière, UPMC, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Benveniste
authors.affiliation: University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Timothy R D J
authors.initials: TRDJ
authors.lastname: Radstake
authors.affiliation: University of Padova, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Doria
authors.affiliation: Ghent University Hospital, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: De Bleecker
authors.affiliation: Ghent University Hospital, Ghent, Belgium.
authors.forename: Boel
authors.initials: B
authors.lastname: De Paepe
authors.affiliation: Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.affiliation: Technische Universität München, Munich, Germany, and Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Technische Universität München, Munich, Germany, and Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.affiliation: Dartmouth College, Hanover, New Hampshire.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: William E
authors.initials: WE
authors.lastname: Ollier
authors.affiliation: Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Feinstein Institute for Medical Research, Manhasset, New York.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Janine A
authors.initials: JA
authors.lastname: Lamb
authors.affiliation: Central Manchester University Hospitals NHS Foundation Trust, University of Manchester, Manchester, UK.
authors.forename: Hector
authors.initials: H
authors.lastname: Chinoy
mesh_terms: D017668:Age of Onset; D001323:Autoantibodies / Q000276:immunology; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D018979:Myositis, Inclusion Body / Q000235:genetics* / Q000276:immunology; D019713:Receptors, CCR5 / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; C584933:CCR5 protein, human; D059811:HLA-DRB1 Chains; D019713:Receptors, CCR5