Genetic factors

Abstract

Systemic sclerosis (SSc) occurs more frequently in families with SSc than in general population. Although clinical concordance between monozygotic twins is poor, their concordance rates are higher for autoantibodies and fibrotic transcript profile. International collaborations have enabled sufficiently powered, genome-wide association studies leading to enormous progress in the field of SSc genetics. In the HLA region, the strongest associations are with the antibody subgroups of SSc. Outside HLA region, over 20 robustly replicated, susceptibility loci have been identified. The majority of these susceptibility loci are involved in innate and adaptive immunity, underscoring the role of immune dysregulation for the SSc pathogenesis. The functional implication of the associated gene variants is often unclear as the majority of them are located in the noncoding regions. These loci might influence directly the transcription of noncoding regulatory RNAs or be in linkage disequilibrium with genetic variants in coding areas. Further functional and fine-mapping studies (including sequencing) are required to elucidate the impact of the associated variants on gene expression and protein production.