Entering a new phase of immunogenetics in the idiopathic inflammatory myopathies

Rothwell, Simon; Cooper, Robert G.; Lamb, Janine A.; Chinoy, Hector

doi:10.1097/01.bor.0000434676.70268.66

Cited by 21 publications

(13 citation statements)

References 29 publications

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“…While the IIM, like other autoimmune diseases, are thought to develop as a consequence of chronic inflammation resulting from environmental exposures in genetically susceptible individuals, few examples of such gene-environment interactions have been reported 30,31 , and none have explained the strong association between AH8.1 and the different myositis phenotypes. The facts that HLA genes: (a) are important in responses to many infectious and noninfectious environmental exposures 32 ; and (b) determine one’s capacity to produce antibodies including many autoantibodies 33 , could explain why specific combinations of HLA alleles are important to the pathogenesis of myositis.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

et al. 2015

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Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis; 473 juvenile dermatomyositis; 532 polymyositis; and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P < 5 × 10−8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1haplotype comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

et al. 2015

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“…7 Genetic interactions are supported by the associations between HLA-DRB1*03 and anti-Jo-1, between HLA-DRB1*11:01 and anti-HMGCR-positive necrotizing autoimmune myositis, and between HLA-DRB1*03:01 and HLA-DRB1*01:01 and inclusion-body myositis. 51 Viruses may be responsible for disrupting immune tolerance, but attempts to amplify viruses -including coxsackieviruses, influenza virus, paramyxoviruses (including mumps virus), cytomegalovirus, and EpsteinBarr virus -from the muscles have failed. [1][2][3][4][5] The best evidence for a viral connection involves retroviruses, because polymyositis or inclusionbody myositis develops in people infected with human immunodeficiency virus (HIV) or human T-cell lymphotropic virus I.…”

Section: Immunopathologymentioning

confidence: 99%

Inflammatory Muscle Diseases

Young¹,

Finn²,

Reisin³

2015

N Engl J Med

140

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“…Systemic lupus erythematosis, Sjogren's syndrome, thrompocytopenia, and sarcoidosis have been reported with IBM. The HLA-DRB1*03:01/*01:01 genotype confers the highest disease risk in inclusion body myositis [19,20] There is no increased risk of myocarditis, interstitial lung disease or malignancy in IBM [21]. …”

Section: Associated Conditionsmentioning

confidence: 99%

Inclusion Body Myositis

2014

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The idiopathic inflammatory myopathies (IIM) are a heterogenous group of rare disorders that share many similarities. In addition to sporadic inclusion body myositis (IBM), these include dematomyositis (DM), polymyositis (PM), and autoimmune necrotizing myopathy (NM). For discussion of later three disorders, the reader is referred to the IIM review in this issue. IBM is the most common IIM after age 50. It typically presents with chronic insidious proximal leg and/or distal arm asymmetric muscle weakness leading to recurrent falls and loss of dexterity. Creatine kinase (CK) is up to 15 times elevated in IBM and needle electromyograhy (EMG) mostly shows a chronic irritative myopathy. Muscle histopathology demonstrates endomysial inflammatory exudates surrounding and invading non-necrotic muscle fibers often times accompanied by rimmed vacuoles and protein deposits. Despite inflammatory muscle pathology suggesting similarity with PM, it likely that IBM is has a prominent degenerative component as supported by refractoriness to immunosuppressive therapy. We review the evolution of our knowledge in IBM with emphasis on recent developments in the field and discuss ongoing clinical trials.

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Entering a new phase of immunogenetics in the idiopathic inflammatory myopathies

Cited by 21 publications

References 29 publications

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes

Inflammatory Muscle Diseases

Inclusion Body Myositis

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