Dr. Hachulla has received consulting fees, speaking fees, and/or honoraria from Pfizer, Actelion, and Roche (less than $10,000 each).
STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis
Article first published online: 30 JUL 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 8, pages 2472–2479, August 2009
How to Cite
Dieudé, P., Guedj, M., Wipff, J., Ruiz, B., Hachulla, E., Diot, E., Granel, B., Sibilia, J., Tiev, K., Mouthon, L., Cracowski, J.L., Carpentier, P.H., Amoura, Z., Fajardy, I., Avouac, J., Meyer, O., Kahan, A., Boileau, C. and Allanore, Y. (2009), STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis. Arthritis & Rheumatism, 60: 2472–2479. doi: 10.1002/art.24688
- Issue published online: 30 JUL 2009
- Article first published online: 30 JUL 2009
- Manuscript Accepted: 18 APR 2009
- Manuscript Received: 25 OCT 2008
- Association des Sclérodermiques de France
- Société Française de Rhumatologie
- Agence Nationale pour la Recherche. Grant Number: R07094KS
- Groupe Française de Recherche sur la Sclérodermie
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.
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.
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 multiplicatively 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 ≥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 = 2.2 × 10−4, OR 1.97, 95% CI 1.28–3.04).
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.