Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis and has been implicated in the pathogenesis of systemic sclerosis (SSc). The aim of the study was to analyse the possible association of CAV1 gene single nucleotide polymorphisms (SNP) with SSc. METHODS: A total population of 3974 individuals (1355 SSc patients, 2619 controls) was studied. Genotype data for 23 SNP spanning the CAV1-CAV2 gene locus were obtained from a genome-wide scan conducted in a French population (564 SSc patients, 1776 controls). Three CAV1 SNP (rs926198, rs959173, rs9920) displaying the most significant associations with SSc and/or clinical phenotypes were then genotyped in an Italian population (791 SSc patients, 843 controls). CAV1 protein expression in skin biopsies was investigated by immunohistochemistry and western blotting. RESULTS: In the French population, the CAV1 rs959173 C minor allele showed a significant protective association with susceptibility to SSc (OR 0.71, 95% CI 0.59 to 0.86, p(adjusted)=0.009), and with the subset of patients with limited cutaneous SSc (OR 0.71, 95% CI 0.56 to 0.89, p(adjusted)=0.018). The association was replicated in the Italian population and strengthened in the combined populations through Cochran-Mantel-Haenszel meta-analysis (SSc: pooled OR 0.81, 95% CI 0.71 to 0.92, p=0.0018; limited cutaneous SSc: pooled OR 0.80, 95% CI 0.69 to 0.93, p=0.0053). Genotype/protein expression correlations revealed that the rs959173 C protective allele was associated with increased CAV1 protein expression. CONCLUSIONS: These results add CAV1 to the list of SSc susceptibility genes and provide further evidence for the contribution of this pathway in the fibrotic process that characterises SSc pathogenesis.
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