Association of a Functional Polymorphism in the Matrix Metalloproteinase-12 Promoter Region with Systemic Sclerosis in an Italian Population

Objective. To investigate the possible implication of the matrix metalloproteinase-12 (MMP-12) gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotype. Methods. The MMP-12 rs2276109 A/G functional polymorphism was selected as a genetic marker and genotyped by polymerase chain reaction-restriction fragment length polymorphism assay in 513 unrelated subjects of Italian white ancestry: 250 patients with SSc [146 limited cutaneous SSc (IcSSc), 104 diffuse cutaneous SSc (dcSSc)] and 263 healthy individuals. Results. A significant difference was observed in MMP-12 rs2276109 genotype distribution between patients with SSc and controls (p = 0.0003), and between IcSSc and dcSSc (p = 0.003). The A allele frequency was significantly higher in patients with SSc than in controls (p = 0.0002), and higher in deSSc than in IcSSc (p = 0.003). After adjustment for age and sex, the homozygosity for the A allele significantly influenced the predisposition to SSc and to deSSc (OR 2.44, 95% CI 1.61-3.71, p < 0.0001; OR 4.69.95% Cl 2.36-9.33, p < 0.0001, respectively). A trend toward an association between the AA genotype and IcSSc was observed (p = 0.06). The homozygosity for the A allele was also significantly and independently associated with antitopoisomerase I antibody positivity (OR 6.39, 95% Cl 2.18-18.76, p = 0.001) and interstitial lung disease (OR 2.94,95% Cl 1.25-6.95, p = 0.01). Conclusion. The MMP-12 rs2276109 gene polymorphism may contribute to susceptibility to SSc, and in particular to dcSSc and pulmonary fibrosis. (First Release July I 2010; J Rheumatol 2010;37:1852-7; (doi:10.3899/jrheum.100237