Immunogenetics of systemic sclerosis: Defining heritability, functional variants and shared-autoimmunity pathways

Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous connective tissue disorder of complex etiology. The development of large-scale genetic studies, such as genome-wide association studies (GWASs) or the Immunochip platform, has achieved remarkable progress in the knowledge of the genetic background of SSc. Herein, we provide an updated picture SSc genetic factors, offering an insight into their role in pathogenic mechanisms that characterize the disease. We review the most recent findings in the HLA region and the well-established non-HLA loci. Up to 18 non-HLA risk factors fulfilled the selected criteria and they were classified according to their role in the innate or adaptive immune response, in apoptosis, autophagy or fibrosis. Additionally, SSc heritability has remained as a controversial question since twin studies provided low SSc heritability estimates. However, we have recalculated the lower bond of narrow sense SSc heritability using GWAS data. Remarkably, our results suggest a greater influence of genetics on SSc than previously reported. Furthermore, we also offer a functional classification of SSc-associated SNPs and their proxies, based on annotated data, to provide clues for the identification of causal variants in these loci. Finally, we explore the genetic overlap between SSc and other autoimmune diseases (ADs). The vast majority of SSc risk loci are shared with at least one additional AD, being the overlap between SSc and systemic lupus erythematous the largest. Nevertheless, we found that an important portion of SSc risk factors are also common to rheumatoid arthritis or primary biliary cirrhosis. Considering all these evidences, we are confident that future research will be successful in understanding the relevant altered pathways in SSc and in identifying new biomarkers and therapeutic targets for the disease.

Keywords: Genetics; Heritability; Polymorphism; Shared loci; Systemic sclerosis.