FOXP3, ICOS and ICOSL polymorphisms in an Italian population affected by systemic sclerosis

Associated with substantial morbidity and mortality rates, systemic sclerosis (SSc) is an autoimmune disorder characterized by vasculopathy, inflammation, progressive perivascular and interstitial fibrosis. SSc pathogenesis is largely unknown, however strong evidences suggest that genetic predisposition may contribute to SSc development. Dysregulation of co-stimulatory and/or co-inhibitory signals, including ICOS signalling, can cause a breakdown of self-tolerance, thus leading to autoimmunity. Furthermore, ICOS has been linked to the function of Tregs. The aim of the present study was to investigate the association between the FOXP3 rs2294020, ICOS rs6726035 and ICOSL rs378299 SNPs and the susceptibility to SSc or to progression from preclinical SSc to definite SSc in a North Italian Caucasian population. Furthermore, we have extended our association analysis of the FOXP3 rs2294020 SNP also in 14 GWAS datasets in order to reveal association between this SNP and susceptibility to other autoimmune diseases in individuals of European ancestry. Autoimmune diseases studied included psoriasis, celiac disease, Crohn s disease, ulcerative colitis, multiple sclerosis, vitiligo, type-1 diabetes, rheumatoid arthritis, and ankylosing spondylitis. Although analysis tests did not show any significant associations between the SNPs under study and SSc, the occurrence of FOXP3 rs2294020 in female patients was associated with an increased risk of progression from early to definite SSc, both in the allelic (HR = 1.43; CI = 1.03-1.99; p=0.03) and in dominant (HR = 1.54; CI = 1.04-2.28; p=0.03) models. The inclusion of presence of ACA, SCL70, and ANA autoantibodies in the model did not significantly change the estimates. Furthermore, the present study shows that rs2204020 may be associated with the susceptibility to autoimmune diseases involving the skin , such as vitiligo and psoriasis (p=0.01 and P=0.038, respectively). In conclusion, this study provides evidence that rs2294020SNP may have a role in SSc evolution, modulating the time of progression from the diagnosis of early SSc to the diagnosis of definite SSc. Moreover, the results of the present study would suggest a potential involvevement of the rs294020 also in other skin-related autoimmune diseases, including vitiligo and psoriasis.