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Title: Determinants of severity and co-morbidity in rheumatoid arthritis : influence of genetic variation and smoking
Author: Chen, Ying
ISNI:       0000 0004 2733 9987
Awarding Body: Keele University
Current Institution: Keele University
Date of Award: 2011
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Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic synovial inflammation, ultimately leading to joint destruction and permanent disability. Disease expression may be affected by genetic variations and environmental factors such as cigarette smoking. The main objective of this study was to identify some of the main determinants of poor outcome in RA, both in terms of disease severity and comorbidity. Analysis of possible interaction of genetic factors with smoking was carried out. Candidate genes included GSTM1, GSTT1, VEGFA, eNOS, MMP1, MMP2, MMP3, TGFB1 and PTPN22. Smoking was associated with seropositive RA, in particular with RF+ RA. It was associated with the development of erosive disease and with more severe functional outcome in seronegative patients. Promoter polymorphism VEGFA-2578(A/C) (rs699947) was associated with serum VEGF-A level, which may reflect a genotype-specific response to inflammation. This polymorphism was associated with disease activity, which only occurred in nonsmokers. The same polymorphism was also associated with the occurrence of IHD and MI, which may be due to an interaction with smoking. Both MMP1 (rs1799750) and MMP3 (rs679629, rs3025058) polymorphisms were independently associated with serum MMP-1 level, whereas serum MMP-3 was mainly associated with MMP3 polymorphisms. MMP3 SNPs were associated with disease activity, independent of systemic inflammation and serum MMP-3. A haplotype across the MMP1-3 loci was associated with the development of erosive disease in earlier RA. Evidence of interaction with smoking was also found regarding the above association. No association of polymorphisms in TGFB1 with serum TGF-β1 level was found. A missense polymorphism TGFB1+868(C/T) (rs1800470) was associated with the occurrence of IHD and MI, which may be explained by an interaction with smoking. The current thesis highlighted the complexity of factors associated with severity and comorbidity in RA, and showed the importance of smoking in exacerbating various aspects of disease outcome.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: R Medicine (General)