A polymorphism in the CTGF promoter region associated with systemic sclerosis.

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.

• Authors: Carmen Fonseca, Gisela E Lindahl, Markella Ponticos, Piersante Sestini, Elisabetta A Renzoni, Alan M Holmes, Paolo Spagnolo, Panagiotis Pantelidis, Patricia Leoni, Neil McHugh, Carmel J Stock, Xu Shi-Wen, Christopher P Denton, Carol M Black, Kenneth I Welsh, Roland M du Bois, David J Abraham
• Journal: The New England journal of medicine (N Engl J Med) Vol. 357 Issue 12 Pg. 1210-20 (Sep 20 2007) ISSN: 1533-4406 [Electronic] United States
• PMID: 17881752 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2007 Massachusetts Medical Society.

Chemical References

• CCN2 protein, human
• Immediate-Early Proteins
• Intercellular Signaling Peptides and Proteins
• Connective Tissue Growth Factor

Topics

• Case-Control Studies
• Connective Tissue Growth Factor
• Female
• Genetic Predisposition to Disease
• Genotype
• Humans
• Immediate-Early Proteins (genetics)
• Intercellular Signaling Peptides and Proteins (genetics)
• Male
• Point Mutation
• Polymerase Chain Reaction
• Polymorphism, Genetic
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Risk Factors
• Scleroderma, Systemic (genetics)
• Sequence Analysis, DNA
• Transcription, Genetic