Updates on genetics in systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a complex disease, in which an interaction of genetic and environmental factors plays an important role in its development and pathogenesis. A number of genetic studies, including candidate gene analysis and genome-wide association study, have found that the associated genetic variants are mainly localized in noncoding regions in the expression quantitative trait locus and influence corresponding gene expression. The gene variants identified as a risk for SSc susceptibility include those associated with innate immunity, adaptive immune response, and cell death, while there are only few SSc-associated genes involved in the fibrotic process or vascular homeostasis. Human leukocyte antigen class II genes are associated with SSc-related autoantibodies rather than SSc itself. Since the pathways between the associated genotype and phenotype are still poorly understood, further investigations using multi-omics technologies are necessary to characterize the complex molecular architecture of SSc, identify biomarkers useful to predict future outcomes and treatment responses, and discover effective drug targets.

Fig. 1

A DRB1 or DRB5 alleles associated with the presence of anti-topo I antibody in various ethnicities and their amino acid sequence at positions 67–71 in the third hypervariable region (HVR). B Proliferative responses of a representative topo I-reactive CD4⁺ T cell clone derived from an anti-topo I-positive patient with SSc in the presence of antigenic peptide-pulsed L cell transfectants expressing a series of human HLA-DR molecules harboring the DRB1 or DRB5 alleles associated with the presence of anti-topo I antibody. The peptide-induced T cell proliferation was measured by ³H-thymidine incorporation