ASSOCIATION OF A FUNCTIONAL POLYMORPHISM IN THE MATRIX METALLOPROTEINASE-12 (MMP-12) PROMOTER REGION WITH SYSTEMIC SCLEROSIS IN AN ITALIAN POPULATION

Background: Systemic sclerosis (SSc) is a life-threatening connective tissue disease characterised by autoimmunity, widespread microvascular involvement and fibrosis of the skin and internal organs. Progressive fibrosis significantly contributes to the morbidity of SSc patients, and interstitial lung disease is a major cause of death. Matrix metalloproteinase-12 (MMP-12) plays an important role in chronic pulmonary inflammation and fibrosis. We have recently shown that dermal fibroblasts and endothelial cells isolated from the skin of patients with diffuse cutaneous SSc (dcSSc) constitutively overexpress and release MMP-12. Interestingly, MMP-12 overproduction by SSc cells has been shown to be a permanent alteration over multiple generations in vitro. The human MMP-12 gene, on chromosome 11q22.3, contains a common A/G functional single-nucleotide polymorphism in the promoter region (rs2276109) which modulates trascriptional activity in an allele-specific manner. The A allele has a greater affinity to the AP-1 transcription factors, thus resulting in increased promoter activity and enhanced MMP-12 expression. Objectives: To investigate the possible association of the MMP-12 gene with susceptibility to SSc. Methods: The MMP-12 rs2276109 polymorphism was selected as genetic marker and genotyped by PCR-RFLP assay in 513 unrelated subjects of Italian Caucasian ancestry: 250 SSc patients (146 with limited cutaneous SSc (lcSSc), 104 with dcSSc) and 263 healthy individuals. Genetic association was assessed by using univariate and multivariate regression analyses. Results: A significant difference in MMP-12 rs2276109 genotype distribution between SSc patients and controls (p=0.0003), and between lcSSc and dcSSc (p=0.003) was observed. The A allele frequency was significantly higher in SSc patients than in controls (p=0.0002), and in dcSSc than in lcSSc (p=0.003). After adjustment for age and sex the homozygosity for the rs2276109 A allele significantly influenced the predisposition to SSc, and in particular to dcSSc (OR 2.44, 95%CI 1.61-3.71, p<0.0001; OR 4.69, 95%CI 2.36-9.33, p<0.0001, respectively). A trend towards an association between the A allele and lcSSc was observed (OR 1.53, 95%CI 0.98-2.39, p=0.06). The homozygosity for the rs2276109 A allele was also significantly and independently associated with anti-topoisomerase I antibody-positivity (OR 6.39, 95%CI 2.18-18.76, p=0.001) and interstitial lung disease (OR 2.94, 95%CI 1.25-6.95, p=0.01) in SSc. Conclusion: The MMP-12 rs2276109 gene polymorphism may contribute to the susceptibility to SSc, and might be an indicator of severe skin and pulmonary fibrosis. Modulation of MMP-12 expression and activity might offer new targeted therapeutic strategies to control the progression of fibrosis in SSc. Disclosure of Interest: None declaredCitation: Annals of the Rheumatic Diseases, volume 69, supplement 3, year 2010, page 413Session: Scleroderma, myositis and related syndromes (Poster Presentations )