STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis

Arthritis Rheum. 2009 Aug;60(8):2472-9. doi: 10.1002/art.24688.


Objective: Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5.

Methods: Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects.

Results: STAT4 rs7574865 was shown to be associated with SSc (P=0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11-1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86-3.99) for combinations of genotypes with >or=3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P=2.2x10(-4), OR 1.97, 95% CI 1.28-3.04).

Conclusion: Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Female
  • France / epidemiology
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Pulmonary Fibrosis / epidemiology
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / genetics*
  • Risk Factors
  • STAT4 Transcription Factor / genetics*
  • Scleroderma, Systemic / complications
  • Scleroderma, Systemic / epidemiology
  • Scleroderma, Systemic / genetics*


  • IRF5 protein, human
  • Interferon Regulatory Factors
  • STAT4 Transcription Factor
  • STAT4 protein, human