Genetic Factors

Systemic sclerosis (SSc) occurs more frequently in families with SSc than in the general population. International collaborations have enabled sufficiently powered, genome-wide association studies, leading to substantial progress in the field of SSc genetics. In the HLA region, the strongest associations are with the antibody subgroups of SSc. Outside the HLA region, up to 30 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. More recently, several loci involved in autophagy and apoptosis have been implicated in SSc susceptibility. The functional implication of the associated gene variants is often unclear as most of them are located in the non-coding regions. These loci might directly influence the transcription of non-coding 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.