A polymorphism in the CTGF promoter region associated with systemic sclerosis

N Engl J Med. 2007 Sep 20;357(12):1210-20. doi: 10.1056/NEJMoa067655.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


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