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Genetic polymorphisms in systemic sclerosis

Fonseca Gutierrez, Maria Del Carmen; (2003) Genetic polymorphisms in systemic sclerosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Systemic Sclerosis (SSc) is a connective tissue disease characterised by vascular damage, immune activation and fibrosis. The pathogenesis of scleroderma is largely unknown, but current evidence supports the role of complex interactions between genetic and environmental factors. The genetic contribution to the disease process is likely to be complex, as SSc cannot be conceptualised as a primary genetic disease. It has been proposed that environmental agent(s) may act as a triggering factor in genetically susceptible individuals. The thesis aims to examine polymorphism within a series of genes that are believed to be involved in the fibrotic process of Scleroderma. This thesis also addresses the relevance of polymorphism with respect to specific Scleroderma characteristics such as disease subsets and autoantibodies association. The candidate genes selected for study in this thesis were: Connective Tissue Growth Factor (CTGF), Endothelin 1, 2 and 3 (EDN-1, -2 and -3), the Endothelin receptors type A (EDNRA) and type B (EDNRB), and collagen type I. Within the collagen gene two regions were examined, the Far upstream enhancer and Collagenase-1 cleavage site within exon 41. The study of polymorphism(s) within these genes were carried out by Polymerase Chain Reaction (PCR) based techniques including, Single Strand Conformational Polymorphism (SSCP), and Sequence Specific Primer-PCR (SSP-PCR). These polymorphisms were studied in a cohort of 151 scleroderma patients, 113 healthy controls, 110 Raynaud's phenomenon (RP) and 26 Autoimmune Raynaud's phenomenon (ARP). A number of interesting associations were suggested between polymorphisms in the studied genes and specific scleroderma features. Notably, the CTGF promoter polymorphism C-743G appeared to be associated with the presence of anti-topoisomerase I antibody in SSc patients and in particular with those patients with concomitant fibrosing alveolitis. The EDN-1 (+138 A I) polymorphism was associated with the presence of anti-RNA polymerase antibody in SSc patients and the K198N T allele presented a negative association in SSc patients without lung fibrosis. The EDNRA (G-231A) polymorphism was associated with the presence of anti-centromere antibody in patients with SSc. Interestingly, no polymorphism was found in the collagen type I Far upstream enhancer region or within the collagenase cleavage site.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Genetic polymorphisms in systemic sclerosis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Sclerosis
URI: https://discovery.ucl.ac.uk/id/eprint/10100816
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