Search

Objective To determine whether the functional BANK1 variants rs3733197 and rs10516487 are associated with systemic sclerosis (SSc) in 2 European Caucasian populations and to investigate the putative gene–gene interactions between BANK1 and IRF5 as well as STAT4. Methods BANK1 single-nucleotide polymorphisms were genotyped in a total population of 2,432 individuals. The French cohort consisted of 874 SSc patients and 955 controls (previously genotyped for both IRF5 rs2004640 and STAT4 rs7574865). The German cohort consisted of 421 SSc patients and 182 controls. Results The BANK1 variants were found to be associated with diffuse cutaneous SSc (dcSSc) in both cohorts, providing an odds ratio (OR) of 0.77 for the rs10516487 T rare allele in the combined populations of dcSSc patients as compared with the combined populations of controls (95% confidence interval [95% CI] 0.64–0.93) and an OR of 0.73 (95% CI 0.61–0.87) for the rs3733197 A rare allele. BANK1 haplotype analysis found the A-T haplotype to be protective in dcSSc patients (OR 0.70 [95% CI 0.57–0.86], P = 3.39 × 10−4) and the G-C haplotype to be a risk factor (OR 1.25 [95% CI 1.06–1.47], P = 0.008). Significant differences were also observed when the limited cutaneous subset of SSc was compared with the dcSSc subset, both for the rare alleles and for the haplotypes. The BANK1, IRF5, and STAT4 risk alleles displayed a multiplicatively increased risk of dcSSc of 1.43-fold. Conclusion Our results establish BANK1 as a new SSc genetic susceptibility factor and show that BANK1, IRF5, and STAT4 act with additive effects.

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 Sjogren'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.

Objective F2-isoprostanes are free radical-dependent arachidonic acid metabolites that are used as clinical markers of lipid peroxidation in systemic sclerosis (SSc) and other microvascular diseases. The objectives of this study were to determine whether the basal urinary levels of F2-isoprostane in SSc patients differ from those in patients with primary Raynaud's phenomenon (RP) and to investigate whether F2-isoprostane formation correlates with the cutaneous microvascular perfusion decrease following cold exposure in SSc patients, patients with primary RP, and healthy controls. Methods Eleven women with RP secondary to SSc, 11 women with primary RP, and 11 healthy women were exposed to decreasing room temperature, from 25°C to 15°C, for 40 minutes. Urine samples were obtained before and after the test for gas chromatography/electronic impact mass spectrometry quantification of 15-F2t-isoprostane (15-F2t-IsoP; also called isoprostaglandin F2α type III). Cutaneous blood flow was monitored using a laser Doppler perfusion imager. Results The mean ± SEM urinary 15-F2t-IsoP levels at baseline in SSc patients (178 ± 32 pmoles/mmole of creatinine) were 1.9 times higher than those in healthy controls (95 ± 11 pmoles/mmole of creatinine) and 1.7 times higher than those in patients with primary RP (107 ± 19 pmoles/mmole of creatinine) (P < 0.05 for controls and patients with primary RP versus SSc patients). No significant correlation was found between basal urinary 15-F2t-IsoP levels and the temperature or cutaneous blood flow decrease in response to the whole-body cooling. Furthermore, the 15-F2t-IsoP response to the cooling test was not correlated with the cutaneous blood flow decrease. Conclusion Lipid peroxidation is increased in SSc patients, but not in patients with primary RP. Cold exposure leads to a significant but small increase in 15-F2t-IsoP levels that is independent of the cutaneous blood flow decrease. F2-isoprostane quantification may be an interesting pharmacologic tool for monitoring responses to antioxidant treatment in SSc patients.

Objective A new family of prostaglandin F2 isomers called F2-isoprostanes, produced by free radical peroxidation of arachidonic acid, has recently been described in vivo. Its quantification has been suggested to be a reliable measure of oxidant injury in vivo. The purpose of this study was to investigate urinary F2-isoprostane formation as an index of lipid peroxidation in scleroderma spectrum disorders. Methods Urine samples were obtained from 52 patients with systemic sclerosis (SSc; n = 37) or undifferentiated connective tissue diseases (UCTD; n = 15) and from 20 healthy volunteers. Urinary isoprostaglandin F2α type III (iPF2α-III) and 11-dehydro thromboxane B2 (11-dehydroTXB2) concentrations were determined using enzyme immunoassays. Results The urinary concentration of iPF2α-III was approximately twice as high in patients (mean ± SEM 229 ± 16 pmoles/mmoles creatinine) as in controls (116 ± 9 pmoles/mmoles creatinine) (P < 0.0001). However, the urinary concentration of iPF2α-III was not significantly different among patients with UCTD, limited SSc, and diffuse SSc (mean ± SEM 221 ± 27 versus 245 ± 32 versus 220 ± 25 pmoles/mmoles creatinine, respectively). No significant correlation was found between the urinary concentrations of iPF2α-III and 11-dehydroTXB2. Conclusion This study provides evidence of enhanced lipid peroxidation in both SSc and UCTD, and suggests a rationale for antioxidant treatment of SSc. Formation of F2-isoprostanes has to be investigated as a means for the evaluation of such therapy.