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

Abstract

ObjectiveInclusion 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.MethodsA 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.ResultsThe 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.ConclusionThis 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.

New Developments in the Genetics of Inclusion Body Myositis

“…Contrary to previous results that HLA-DRB4 is protective and ameliorates the risk effect of HLA-DRB1*03:01 [17], no HLA alleles were found to modify disease onset or severity of IBM in this study. Furthermore, in agreement with a study performed in an Australian cohort, there was no distinct HLA association with anti-cytosolic 5’-nucleotidase 1A (anti-cN1A) positivity [19,23]. …”

“…Nonetheless, since first described by Garlepp et al in 1994, the Human Leukocyte Antigen (HLA) locus has been shown repeatedly to contain the strongest risk alleles for the development of IBM (Table 1) [16–19]. Recently, the Myositis Genetics Consortium (MYOGEN) analyzed immune-related genes in 252 Caucasian IBM patients and 1,008 ethnically-matched controls from 11 countries using the Illumina Immunochip array [19]. Variants within the HLA locus were the only single-nucleotide polymorphisms (SNPs) to reach genome-wide significance (p < 5 × 10 −8 ).…”

“…Of note, previous studies have associated positions 11 and 26 with other autoimmune diseases such as systemic lupus erythematosus [24]. Both of these residues are located within the β-sheet floor of DR β-chain 1 that forms part of the peptide-binding groove and may influence peptide binding and predispose individuals to autoimmunity [19]. Interestingly, although HLA-DRB1*03:01 is also a significant risk factor for Polymyositis (PM) and Dermatomyositis (DM), amino acid position 74 explains almost all of the risk within the allele for PM and DM [25].…”

Genetics in inclusion body myositis

“…Recent studies suggest that several autoimmune diseases, including the IIMs, share genetic overlap for susceptibility to disease [ 14 , 15 ]. In line with this evidence, a recent study hypothesized that there may be shared immune loci associated with IBM [ 16 ▪▪ ].…”

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

“…8 Written informed consent was obtained from all patients with approval from research ethics committees of institutional review boards at each participating centre. Patients were enrolled in to MYOGEN if they fulfilled Bohan and Peter criteria for PM and adult and juvenile DM,8 or Griggs, Medical Research Council (MRC) or European Neuromuscular Centre (ENMC) criteria for patients with IBM 14. Shared control genotypes were drawn from a pool of 15 651 individuals from 12 countries as described previously 8.…”