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A polymorphism in the CTGF promoter region associated with systemic sclerosis

Fonseca, C; Lindahl, GE; Ponticos, M; Sestini, P; Renzoni, EA; Holmes, AM; Spagnolo, P; ... Abraham, DJ; + view all (2007) A polymorphism in the CTGF promoter region associated with systemic sclerosis. NEW ENGL J MED , 357 (12) 1210 - 1220. Green open access

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Abstract

BackgroundSystemic sclerosis (scleroderma) is a life-threatening autoimmune disease that is characterized by the presence of specific autoantibodies and fibrosis of the skin and major internal organs.MethodsWe genotyped a polymorphism (G-945C) in the promoter of the connective-tissue growth factor (CTGF) gene in 1000 subjects in two groups: group 1, consisting of 200 patients with systemic sclerosis and 188 control subjects; and group 2, consisting of 300 patients with systemic sclerosis and 312 control subjects. The combined groups represented an estimated 10% of patients with systemic sclerosis in the United Kingdom. We tested the effect of the polymorphism on the transcription of CTGF.ResultsThe GG genotype was significantly more common in patients with systemic sclerosis than in control subjects in both groups, with an odds ratio for the combined group of 2.2 (95% confidence interval [CI], 1.5 to 3.2; P<0.001 for trend). Analysis of the combined group of patients with systemic sclerosis showed a significant association between homozygosity for the G allele and the presence of anti-topoisomerase I antibodies (odds ratio, 3.3; 95% CI, 2.0 to 5.6; P<0.001) and fibrosing alveolitis (odds ratio, 3.1; 95% CI, 1.9 to 5.0; P<0.001). We observed that the substitution of cytosine for guanine created a binding site of the transcriptional regulators Sp1 and Sp3. The C allele has high affinity for Sp3 and is associated with severely reduced transcriptional activity. A chromatin immunoprecipitation assay showed a marked shift in the ratio of Sp1 to Sp3 binding at this region, demonstrating functional relevance in vivo.ConclusionsThe G-945C substitution represses CTGF transcription, and the -945G allele is significantly associated with susceptibility to systemic sclerosis.

Type: Article
Title: A polymorphism in the CTGF promoter region associated with systemic sclerosis
Open access status: An open access version is available from UCL Discovery
Additional information: The credit line should read as follows: “From NEW ENGL J MED, Fonseca, C; Lindahl, GE; Ponticos, M; Sestini, P; Renzoni, EA; Holmes, AM; Spagnolo, P;, A polymorphism in the CTGF promoter region associated with systemic sclerosis, 357, 1210-1220. Copyright © 2007 Massachusetts Medical Society. Reprinted with permission.
Keywords: TISSUE GROWTH-FACTOR, SCLERODERMA FIBROBLASTS, GENE, EXPRESSION, DISEASE, ANTICENTROMERE, AUTOANTIBODIES, SP1, DNA, ACTIVATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: http://discovery.ucl.ac.uk/id/eprint/1305479
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