ASSOCIATION OF FAS-G670A GENE POLYMORPHISM WITH SYSTEMIC SCLEROSIS

Background: Systemic sclerosis (SSc) is an autoimmune disease affecting the skin and various internal organs, in which T cell activation and resistance to apoptosis play a pivotal role. Apoptosis is a physiologic process that regulates normal homeostasis and likely contributes to the pathogenesis of autoimmunity by impairing the deletion of autoreactive immune cells. FAS, also known as Apo-1/CD95, is a cell-surface receptor belonging to the TNF receptor superfamily, involved in cell-death signaling. The FAS gene is highly polymorphic, particularly in its promoter region. One of these polymorphisms is caused by a G to A base change at nucleotide -670 in the enhancer region, and it was recently found to be associated with rheumatoid arthritis and systemic lupus erythematosus. This mutation abolishes the binding site of the nuclear transcription element GAS (interferon-Gamma-Activated Sequence) and, likely, alters the expression of the FAS gene and the FAS-mediated apoptotic signaling.Objectives: In this study we assessed the presence of the FAS-G670A polymorphism and its relationship with several clinical items of the disease in a multicentric Italian Caucasian population of SSc patients.Methods: We studied 159 SSc patients, 50 with the diffuse (dcSSc) and 109 with the limited (lcSSc) cutaneous form of the disease, and 115 ethnically, age and sex-matched healthy controls. Genomic DNA was extracted from the pheripheral blood of each subject and the FAS-G670A polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Genotype and allelic frequencies were compared between patients and controls using a chi test. Associations were expressed as odds ratios (OR) with 95% confidence interval (95% CI). A p value less than 0.05 was considered statistically significant.Results: The distribution of genotypes in patients and controls was consistent with Hardy-Weinberg equilibrium. A significant difference in genotype distribution for the FAS-G670A polymorphism was observed between SSc patients and controls (GG: 18.9% vs 21.7%, GA: 40.9% vs 53.9%, AA: 40.2% vs 24.3%, chi=7.75, p=0.02). With regard to the FAS allelic frequency, we found a significantly higher prevalence of the FAS-670A allele in patients than in controls (61% vs 51%, chi=4.79, p=0.02). In univariate analysis, by using a recessive model of inheritance (AA vs GA+GG), FAS-670AA genotype influenced the predisposition to SSc (OR=2.09, 95% CI: 1.23-3.56, p=0.006). No significant differences in genotype distribution and allelic frequency were observed between dcSSc and lcSSc patients, although we observed an higher prevalence of the FAS-670A allele in dcSSc patients (67% vs 58%, chi=2.44, p=0.1).Conclusion: Our preliminary results demonstrate a close association between the FAS-G670A polymorphism and the susceptibility to SSc in Italian Caucasian patients.Citation: Ann Rheum Dis, volume 66, supplement II, year 2007, page 211Session: Scleroderma, myositis and related syndromes