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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.

Key Points

  • Innovations in genotyping technology such as candidate gene studies and genome-wide association studies (GWAS) have advanced our understanding of the genetic basis of systemic lupus erythematosus (SLE)

  • GWAS and candidate gene studies using both European and Asian populations identified and confirmed more than 30 robust SLE susceptibility loci

  • Genetic associations identified in various ethnic groups not only highlight major SLE susceptibility genes that are common to multiple ethnic populations, but also indicate those loci with population-specific effects

  • Most SLE-associated gene products participate in key pathways involved in the disease pathogenesis and genetic risk factors that are shared between autoimmune diseases can help to identify common disease pathways

  • Novel SLE risk loci can reveal new paradigms for the pathogenesis of the disease, and might provide new therapeutic targets for disease management

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Figure 1: Model of SLE-associated genetic variants in the immune response.

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Both authors contributed equally to researching data for the article, providing a substantial contribution to discussions of the content, writing the article and to review and/or editing of the manuscript before submission.

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Correspondence to Betty P. Tsao.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Comparison of GWAS findings between European and Asian populations (DOC 162 kb)

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Deng, Y., Tsao, B. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol 6, 683–692 (2010). https://doi.org/10.1038/nrrheum.2010.176

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