High-resolution HLA-DRB1 genotyping in an Australian inclusion body myositis (s-IBM) cohort: An analysis of disease-associated alleles and diplotypes

Rojana-udomsart, Arada; James, Ian; Castley, Alison; Needham, Merrilee; Scott, Adrian P.; Day, Timothy; Kiers, Lynette; Corbett, Alastair; Sue, Carolyn M.; Witt, Campbell S.; Martínez, Patricia; Christiansen, Frank; Mastaglia, Frank

doi:10.1016/j.jneuroim.2012.05.003

Cited by 33 publications

(24 citation statements)

References 27 publications

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“…This association has subsequently been confirmed in a series of further studies in Caucasians with HLA-A*01, -B*0801, -DRB1*0301, -DRB1*0101, -DRB1*1301, -DQB1*0201, -DQA1*05 [58-65]. Furthermore, Rojana-udomsart and colleagues reported that the risk factors HLA-DRB1*0301 and *1301 also influence on the age at onset and the severity of muscle weakness [65]. These results indicate that the interactions at HLA-DRB1 locus may contribute to both disease susceptibility and clinical phenotype.…”

Section: Pathogenesis Of Sibm and Its Predisposing Genetic Factorsmentioning

confidence: 65%

Sporadic inclusion body myositis: the genetic contributions to the pathogenesis

Gang

Bettencourt

Machado

et al. 2014

Orphanet Journal of Rare Diseases

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Sporadic inclusion body myositis (sIBM) is the commonest idiopathic inflammatory muscle disease in people over 50 years old. It is characterized by slowly progressive muscle weakness and atrophy, with typical pathological changes of inflammation, degeneration and mitochondrial abnormality in affected muscle fibres. The cause(s) of sIBM are still unknown, but are considered complex, with the contribution of multiple factors such as environmental triggers, ageing and genetic susceptibility. This review summarizes the current understanding of the genetic contributions to sIBM and provides some insights for future research in this mysterious disease with the advantage of the rapid development of advanced genetic technology. An international sIBM genetic study is ongoing and whole-exome sequencing will be applied in a large cohort of sIBM patients with the aim of unravelling important genetic risk factors for sIBM.

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Section: Pathogenesis Of Sibm and Its Predisposing Genetic Factorsmentioning

confidence: 65%

Sporadic inclusion body myositis: the genetic contributions to the pathogenesis

Gang

Bettencourt

Machado

et al. 2014

Orphanet Journal of Rare Diseases

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“…Whereas in AD apolipoprotein APOE ε4 is a strong risk factor 5 , in s-IBM there is no recognised association with APOE genotype 6,7 , although APOE has been shown to colocalise with β-amyloid in vacuolated muscle fibres 8 . The strongest genetic association in s-IBM is with the HLA-DRB1 and secondary HLA-DRB loci in the central MHC region [9][10][11] . In addition, in a phylogenetic analysis of mtDNA variants we demonstrated an association with the 4336G and 4580A D-loop variants in s-IBM, but not in AD 12 .…”

Section: Introductionmentioning

confidence: 99%

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

Mastaglia

Rojana-udomsart

James

et al. 2013

Neuromuscular Disorders

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Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms.Neuromuscular Disorders, 23 (12 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractA polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer's disease and APOE-TOMM40genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer's disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90Caucasian s-IBM patients (55 males; age 69.1± 9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective.Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.

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“…Other HLA–DRB1 alleles such as HLA–DRB1*01:01 and HLA–DRB1*13:01 have also been implicated in IBM, and genotypic combinations of these alleles have been reported to correlate with clinical phenotype 5.…”

mentioning

confidence: 99%

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

Rothwell

Cooper

Lundberg

et al. 2017

Arthritis & Rheumatology

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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.

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High-resolution HLA-DRB1 genotyping in an Australian inclusion body myositis (s-IBM) cohort: An analysis of disease-associated alleles and diplotypes

Cited by 33 publications

References 27 publications

Sporadic inclusion body myositis: the genetic contributions to the pathogenesis

Sporadic inclusion body myositis: the genetic contributions to the pathogenesis

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

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

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