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Previous Volume 357:1210-1220 September 20, 2007 Number 12 Next

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ABSTRACT

Background Systemic 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.

Methods We 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.

Results The 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.

Conclusions The G–945C substitution represses CTGF transcription, and the –945G allele is significantly associated with susceptibility to systemic sclerosis.

Source Information

From the Centre for Rheumatology, Royal Free and University College Medical School, London (C.F., G.E.L., M.P., A.M.H., P.L., C.J.S., X.S.-W., C.P.D., C.M.B., D.J.A.); the Institute of Respiratory Diseases, University of Siena, Siena, Italy (P. Sestini); the Clinical Genomics Group, National Heart and Lung Institute, Imperial College London, London (E.A.R., P. Spagnolo, P.P., K.I.W., R.M.B.); and the Royal National Hospital for Rheumatic Diseases, Centre for Rheumatology, Bath, United Kingdom (N.M.).

Drs. Fonseca and Lindahl contributed equally to this article.

Address reprint requests to Dr. Abraham at the Department of Rheumatology, University College London, Hampstead Campus, Rowland Hill St., London NW3 2PF, United Kingdom, or at d.abraham{at}medsch.ucl.ac.uk.

Full Text of this Article

Related Letters:

CTGF Polymorphism Associated with Systemic Sclerosis
Morita H., Hayashi D., Nagai R., Gourh P., Mayes M. D., Arnett F. C., Fonseca C., Pantelidis P., Abraham D.
Extract | Full Text | PDF  
N Engl J Med 2008; 358:308-309, Jan 17, 2008. Correspondence

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