Genetic susceptibility to systemic lupus erythematosus in the genomic era

Abstract

Our understanding of the genetic basis of systemic lupus erythematosus (SLE) has been rapidly advanced using large-scale, case-control, candidate gene studies as well as genome-wide association studies during the past 3 years. These techniques have identified more than 30 robust genetic associations with SLE including genetic variants of HLA and Fcγ receptor genes, IRF5, STAT4, PTPN22, TNFAIP3, BLK, BANK1, TNFSF4 and ITGAM. Most SLE-associated gene products participate in key pathogenic pathways, including Toll-like receptor and type I interferon signaling pathways, immune regulation pathways and those that control the clearance of immune complexes. Disease-associated loci that have not yet been demonstrated to have important functions in the immune system might provide new clues to the underlying molecular mechanisms that contribute to the pathogenesis or progression of SLE. Of note, genetic risk factors that are shared between SLE and other immune-related diseases highlight common pathways in the pathophysiology of these diseases, and might provide innovative molecular targets for therapeutic interventions.

Figure 1

Model of SLE-associated genetic variants in the immune response. This model is derived from current understandings of important immunological pathways involved in SLE pathogenesis, as highlighted by the identified SLE susceptibility loci. a | Processing and clearance of immune complexes. Environmental triggers that induce apoptosis and release of nuclear antigens can stress phagocytes (including macrophages and neutrophils), causing defective clearance of nuclear antigens. b | TLR–IFN signaling. Environmental triggers including ultraviolet light, demethylating drugs and viruses can yield stimulatory DNA or RNA that activates TLRs, resulting in secretion of type I IFN. c | Signal transduction in the adaptive immune response. Presentation of nuclear antigens to dendritic cells leads to the generation of autoantibodies and immune complexes that amplify both innate and adaptive immune responses. Abbreviations: BCR, B-cell receptor; IFN, interferon; IL, interleukin; SLE, systemic lupus erythematosus; TCR, T-cell receptor; TLR, Toll-like receptor.