Abstract

Many identified genetic risk factors for systemic lupus erythematosus (SLE) contribute to the function of the immune system, which has expanded our understanding of disease pathogenesis. We outline the genetic variants in recently identified SLE-associated loci, the immunological pathways affected by these gene products and the disease manifestations linked to these loci. Pathways potentially influenced by SLE risk variants include: apoptosis, DNA degradation and clearance of cellular debris; antigen presentation; type I interferon, Toll-like receptor and nuclear factor kappa κB activation; defective clearance of immune complexes containing nuclear antigens; B and T-cell function and signalling; and monocyte and neutrophil function and signalling. These identified SLE susceptibility loci are predominantly common variants that have been confirmed among multiple ancestries, suggesting shared mechanisms in disease aetiology. Ongoing genetic studies continue the investigation of specific functional variants, and their potential consequences on immune dysregulation, enhancing our understanding of links between genotypes and specific disease manifestations. The next generation of sequencing explores the identification of causal rare variants that may contribute robust genetic effects to developing SLE. Novel insights coming from genetic studies of SLE provide the opportunity to elucidate pathogenic mechanisms as well as contribute to the development of innovative therapeutic targets for this complex disease.