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Title: Identification of disease susceptibility genes in the idiopathic inflammatory myopathies
Author: Rothwell, Simon
ISNI:       0000 0004 5372 5216
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2016
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Background: The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of rare autoimmune diseases comprising of polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM). They are characterised primarily by muscle weakness, and can present with extramuscular manifestations such as skin rashes, interstitial lung disease and malignancy. Aims: This aim of this study was to identify novel genetic risk factors in IIM and to further elucidate the relationship between genotype and serotype. Methods: 2,566 IIM samples were collected from 14 countries through the Myositis Genetics Consortium (MYOGEN) and genotyped on the Immunochip, a custom array covering 186 established autoimmune susceptibility loci. SNP2HLA was used to impute classical HLA alleles and constituent amino acids. Results: In a combined IIM analysis, the HLA region and PTPN22 reached genome-wide significance (p<5x10-8). A further nine regions reached suggestive significance (p<2.25x10-5) including UBE2L3, STAT4 and CD28 that have been implicated in autoimmune disease previously. Independent effects were seen within the STAT4 region. In a PM subgroup analysis (n=931), the HLA region and PTPN22 reached genome-wide significance. A further seven regions reached suggestive significance including SLC26A1/IDUA and RGS1. In an adult and juvenile DM analysis (n=1,360), only the HLA region reached genome wide significance. Three loci reached suggestive significance including GSDMB. In the IBM analysis (n=252), only the HLA region reached genome wide significance and 3 loci reached suggestive significance, including the CCR2 locus. Identification of exonic and eQTL SNPs has localised association signals to several potential causal variants. HLA imputation on the combined dataset confirmed that alleles of the 8.1 ancestral haplotype (AH) are most strongly associated with IIM. The cohort was stratified in to clinical subgroups. In PM the strongest effect was found with HLA-DRB1*03:01 with an independent effect with HLA-B*08:01. Amino acid position 74 lies within the peptide binding groove and may explain the risk in HLA-DRB1. HLA-B*08:01 was the most associated variant in both DM and JDM, with independent effects of amino acid position 57 of HLA-DQB1 in DM and HLA-C*02:02 in JDM. In IBM, the strongest associations were with amino acids positions 26 and 11 of HLA-DRB1.HLA imputation was conducted on antibody subgroups. The most associated variant for anti-Jo-1 and anti-PM/Scl antibodies was with amino acid 74 of HLA-DRB1. Alleles of the 8.1 AH were most associated with anti-TIF1-γ, anti-SAE and anti-cN1A antibodies. Alleles independent of the 8.1 AH were replicated such as anti-Mi-2 antibodies and HLA-DRB1*07:01, and anti-HMGCR antibodies and HLA-DRB1*11. Conclusions: This represents the largest study to date in IIM and has considerably expanded our knowledge about the genetic architecture of this rare disease. This study has identified novel disease susceptibility genes for IIM and independent associations with PM and DM, IBM and antibody subgroups that show that stratifying patients in to more homogenous cohorts is important to expand our knowledge of IIM. Ongoing sample collection is required to identify additional genes and environmental risk factors that lead to the development of IIM, and to expand our limited understanding of the pathogenesis of this disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Genetics ; Idiopathic Inflammatory Myopathies ; Myositis