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The -670G>A polymorphism in the FAS gene promoter region influences the susceptibility to systemic sclerosis
  1. Vasiliki Liakouli (vasiliki_liakouli{at}yahoo.it)
  1. Dept. of Internal Medicine and Public Health, University of L’Aquila, L’Aquila, Italy, Italy
    1. Mirko Manetti (mirkomanetti{at}yahoo.it)
    1. Dept. of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy, Italy
      1. Alessandra Pacini (alessandra.pacini{at}unifi.it)
      1. Dept. of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy, Italy
        1. Barbara Tolusso (barbara.tolusso{at}rm.unicatt.it)
        1. Division of Rheumatology, Catholic University of Rome, Rome, Italy;, Italy
          1. Cinzia Fatini (cinzia.fatini{at}unifi.it)
          1. Dept. of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy
            1. Annarita Toscano (annaritatoscano{at}hotmail.com)
            1. Dept. of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy, Italy
              1. Paola Cipriani (paolacipriani{at}tiscali.it)
              1. Dept. of Internal Medicine and Public Health, University of L’Aquila, L’Aquila, Italy, Italy
                1. Serena Guiducci (serena16{at}libero.it)
                1. Dept. of Biomedicine, Division of Rheumatology, University of Florence, Florence, Italy, Italy
                  1. Laura Bazzichi (l.bazzichi{at}int.med.unipi.it)
                  1. Division of Rheumatology, University of Pisa, Pisa, Italy, Italy
                    1. Veronica Codullo (veronicacodullo{at}yahoo.it)
                    1. Division of Rheumatology, University of Pavia, Pavia, Italy, Italy
                      1. Luigia Ruocco (luigia.ruocco{at}virgilio.it)
                      1. Division of Rheumatology, II University of Naples, Naples, Italy, Italy
                        1. Luigi Dell’Orso (luigi.dellorso{at}tin.it)
                        1. Immunohematologic and Transfusional Centre, San Salvatore Hospital, L’Aquila, Italy, Italy
                          1. Francesco Carubbi (francescocarubbi{at}libero.it)
                          1. Dept. of Internal Medicine and Public Health, University of L’Aquila, L’Aquila, Italy, Italy
                            1. Alessandra Marrelli (alessandramarrelli{at}tiscali.it)
                            1. Dept. of Internal Medicine and Public Health, University of L’Aquila, L’Aquila, Italy, Italy
                              1. Rosanna Abbate (r.abbate{at}dfc.unifi.it)
                              1. Dept. of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy
                                1. Stefano Bombardieri (s.bombardieri{at}int.med.unipi.it)
                                1. Division of Rheumatology, University of Pisa, Pisa, Italy, Italy
                                  1. Gianfranco Ferraccioli (gf.ferraccioli{at}rm.unicatt.it)
                                  1. Division of Rheumatology, Catholic University of Rome, Rome, Italy, Italy
                                    1. Carlomaurizio Montecucco (montecucco{at}smatteo.pv.it)
                                    1. Division of Rheumatology, University of Pavia, Pavia, Italy, Italy
                                      1. Gabriele Valentini (gabriele.valentini{at}unina2.it)
                                      1. Division of Rheumatology, II University of Naples, Naples, Italy, Italy
                                        1. Marco Matucci-Cerinic (cerinic{at}unifi.it)
                                        1. Dept. of Biomedicine, Division of Rheumatology, University of Florence, Florence, Italy, Italy
                                          1. Lidia Ibba-Manneschi (ibba{at}unifi.it)
                                          1. Dept. of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy, Italy
                                            1. Roberto Giacomelli (roberto.giacomelli{at}cc.univaq.it)
                                            1. Dept. of Internal Medicine and Public Health, University of L’Aquila, L’Aquila, Italy, Italy

                                              Abstract

                                              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.

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