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Title: A correlation of genotype and phenotype in myositis
Author: Chinoy, Hector
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2007
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Aims: To elucidate the aetiopathological mechanisms underlying the IIMs, through a combination of genotyping, serotyping and clinical phenotyping in a large cohort of Caucasian idiopathic inflammatory myopathy (IIM) patients. Methods: A cross-sectional study of prevalent IIM cases, ascertained through the Adult Onset Myositis Immunogenetic Collaboration, was performed. Cases were confirmed as possessing myositis according to Bohan and Peter (Bohan and Peter 1975a; Bohan and Peter 1975b). IIM clinical subtypes studied included polymyositis (PM), dermatomyositis (DM) and myositis associated with other connective tissue disease (myositis/CTD-overlap). Genotyping of major histocompatibility complex genes, including HLA-B, -DR, -DQ, tumour necrosis factor alpha (TNF-α), was performed using commercial kits. Serotyping of a comprehensive range of myositis specific/associated antibodies (MSA/MAAs) was undertaken. Results: Clinical subsets are described within the serological groupings, suggesting that the classification of the IIMs appears to be better served by the serotype than by the clinical subgrouping of disease. The IIMs possess HLA class I and II haplotype associations and genetic differences observed between PM and DM are accounted for by serological differences. The TNF-308A association is not independent of HLA class I, due to the strong LD within the MHC, but does form part of a haplotype with these factors. An absence of routinely tested for MSA/MAAs makes cancer associated myositis (CAM) more likely, especially in the DM subgroup. An antibody against a 155 and 140kDa doublet is associated with the development of CAM. Outcome measures in the IIMs show construct validity. HLA-DRB1*07 appears to predict a milder clinical phenotype with less disability. No convincing gene-environmental interaction was found capable of altering disease susceptibility or clinical phenotype. Conclusions: Myositis disease subtypes therefore appear to be defined by specific haplotypes acting as risk factors for the development of various MSAs and MAAs.
Supervisor: Cooper, Robert G.; Ollier, William E. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Myositis ; Dermatomyositis ; Polymyositis ; HLA ; Polymorphisms ; Genetic association studies ; TNF ; Malignancy ; 155/140