Objective: To evaluate the role of the single-nucleotide polymorphism (SNP) at position -670 in the FAS gene promoter (FAS-670G>A) in influencing the susceptibility, the clinical features and the severity of systemic sclerosis (SSc).
Methods: We studied 350 Italian Caucasian SSc patients (259 with limited cutaneous SSc [lcSSc] and 91 with diffuse cutaneous SSc [dcSSc]) and 232 healthy subjects. Patients were assessed for the presence of autoantibodies (anticentromere, anti-topoisomerase I [anti-Scl-70] antibodies), interstitial lung disease (ILD), pulmonary arterial hypertension and scleroderma renal crisis. FAS-670G>A SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum levels of soluble FAS were analysed by ELISA.
Results: A significant difference in FAS-670 genotype distribution was observed between SSc patients and healthy subjects (P=0.0012). The frequency of FAS-670A allele was significantly higher in SSc than in controls (P=0.0004). No significant difference in genotype distribution and allele frequencies was observed between lcSSc and dcSSc, although a higher frequency of FAS-670A allele in dcSSc was found. FAS-670AA genotype significantly influenced the predisposition to SSc (OR 1.97, 95%CI 1.35-2.88, P=0.0004), and to both lcSSc (OR 1.84, 95%CI 1.23-2.75, P=0.003) and dcSSc (OR 2.37, 95%CI 1.41-3.99, P=0.001). FAS-670A allele frequency was higher, although not significantly, in anti-Scl-70 antibody-positive dcSSc and in ILD dcSSc. Soluble FAS was significantly higher in patients and controls carrying FAS-670AA genotype compared with those carrying FAS-670GG genotype (P=0.003).
Conclusion: The FAS-670A allele is significantly associated with susceptibility to SSc, suggesting a role for a genetic control of apoptosis in the pathogenesis of the disease.