Objective: There is now growing evidence that connective tissue diseases, including systemic sclerosis (SSc), share a common genetic background. Microarray studies support a pivotal role of type I interferon (IFN) in the pathophysiology of connective tissue diseases. Interferon regulatory factors coordinate the expression of type I IFNs, and the IRF5 gene has been identified as a susceptibility gene of systemic lupus and Sjögren's syndrome. The aim of this study was to determine whether the IRF5 rs2004640 single-nucleotide polymorphism is associated with SSc.
Methods: The IRF5 rs2004640 (GT) functional polymorphism was genotyped in 1,641 subjects of French European Caucasian origin: a discovery set comprising 427 patients with SSc and 380 control subjects and a replication set comprising 454 patients with SSc and 380 control subjects.
Results: In both the discovery set and the replication set, the TT genotype was significantly more common in patients with SSc than in control subjects, with an odds ratio (OR) for the combined populations of 1.58 (95% confidence interval [95% CI] 1.18-2.11 [P for trend 0.002]). Analyses of the whole SSc population showed a significant association between homozygosity for the T allele and the presence of antinuclear antibodies (corrected P [Pcorr]=0.04, OR 1.59, 95% CI 1.16-2.17) and fibrosing alveolitis (Pcorr=0.001, OR 2.07, 95% CI 1.38-3.11). In a multivariate analysis model including the diffuse cutaneous subtype of SSc and positivity for anti-topoisomerase I antibodies, the IRF5 rs2004640 TT genotype remained associated with fibrosing alveolitis (P=0.029, OR 1.92, 95% CI 1.07-3.44).
Conclusion: The IRF5 rs2004640 GT substitution is associated with susceptibility to SSc. These data provide new insight into the pathogenesis of SSc, including clues to the mechanisms leading to fibrosing alveolitis.