Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Recent insights into the genetic basis of systemic lupus erythematosus

Abstract

Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcγ receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Deapen D, Escalante A, Weinrib L, Horwitz D, Bachman B, Roy-Burman P et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992; 35: 311–318.

    Article  CAS  PubMed  Google Scholar 

  2. Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, Caeiro F, Massardo L, Villa AR et al. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum 2005; 52: 1138–1147.

    Article  PubMed  Google Scholar 

  3. Hochberg MC . The application of genetic epidemiology to systemic lupus erythematosus. J Rheumatol 1987; 14: 867–869.

    CAS  PubMed  Google Scholar 

  4. Lawrence JS, Martins CL, Drake GL . A family survey of lupus erythematosus. 1. Heritability. J Rheumatol 1987; 14: 913–921.

    CAS  PubMed  Google Scholar 

  5. Sestak AL, Shaver TS, Moser KL, Neas BR, Harley JB . Familial aggregation of lupus and autoimmunity in an unusual multiplex pedigree. J Rheumatol 1999; 26: 1495–1499.

    CAS  PubMed  Google Scholar 

  6. Block SR . A brief history of twins. Lupus 2006; 15: 61–64.

    Article  CAS  PubMed  Google Scholar 

  7. Graham RR, Kyogoku C, Sigurdsson S, Vlasova IA, Davies LR, Baechler EC et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci USA 2007; 104: 6758–6763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fernando MM, Stevens CR, Sabeti PC, Walsh EC, McWhinnie AJ, Shah A et al. Identification of two independent risk factors for lupus within the MHC in United Kingdom families. PLoS Genet 2007; 3: e192.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jacob CO, Reiff A, Armstrong DL, Myones BL, Silverman E, Klein-Gitelman M et al. Identification of novel susceptibility genes in childhood-onset systemic lupus erythematosus using a uniquely designed candidate gene pathway platform. Arthritis Rheum 2007; 56: 4164–4173.

    Article  CAS  PubMed  Google Scholar 

  10. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 2008; 40: 204–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med 2008; 358: 900–909.

    Article  CAS  PubMed  Google Scholar 

  12. Nath SK, Han S, Kim-Howard X, Kelly JA, Viswanathan P, Gilkeson GS et al. A nonsynonymous functional variant in integrin-alpha(M) (encoded by ITGAM) is associated with systemic lupus erythematosus. Nat Genet 2008; 40: 152–154.

    Article  CAS  PubMed  Google Scholar 

  13. Kozyrev SV, Abelson AK, Wojcik J, Zaghlool A, Linga Reddy MV, Sanchez E et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 2008; 40: 211–216.

    Article  CAS  PubMed  Google Scholar 

  14. Sawalha AH, Webb R, Han S, Kelly JA, Kaufman KM, Kimberly RP et al. Common variants within MECP2 confer risk of systemic lupus erythematosus. PLoS ONE 2008; 3: e1727.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Graham DS, Graham RR, Manku H, Wong AK, Whittaker JC, Gaffney PM et al. Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus. Nat Genet 2008; 40: 83–89.

    Article  PubMed  Google Scholar 

  16. Graham RR, Cotsapas C, Davies L, Hackett R, Lessard CJ, Leon JM et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet 2008; 40: 1059–1061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008; 40: 955–962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Baechler EC, Gregersen PK, Behrens TW . The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol 2004; 16: 801–807.

    Article  CAS  PubMed  Google Scholar 

  19. Crow MK, Kirou KA . Interferon-alpha in systemic lupus erythematosus. Curr Opin Rheumatol 2004; 16: 541–547.

    Article  CAS  PubMed  Google Scholar 

  20. Cunninghame Graham DS, Manku H, Wagner S, Reid J, Timms K, Gutin A et al. Association of IRF5 in UK SLE families identifies a variant involved in polyadenylation. Hum Mol Genet 2007; 16: 579–591.

    Article  CAS  PubMed  Google Scholar 

  21. Kozyrev SV, Lewen S, Reddy PM, Pons-Estel B, Witte T, Junker P et al. Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus. Arthritis Rheum 2007; 56: 1234–1241.

    Article  CAS  PubMed  Google Scholar 

  22. Kelly JA, Kelley JM, Kaufman KM, Kilpatrick J, Bruner GR, Merrill JT et al. Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. Genes Immun 2008; 9: 187–194.

    Article  CAS  PubMed  Google Scholar 

  23. Jacob CO, Zhu J, Armstrong DL, Yan M, Han J, Zhou XJ et al. Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci USA 2009; 106: 6256–6261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357: 977–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Taylor KE, Remmers EF, Lee AT, Ortmann WA, Plenge RM, Tian C et al. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet 2008; 4: e1000084.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Levy DE, Darnell Jr JE . Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002; 3: 651–662.

    Article  CAS  PubMed  Google Scholar 

  27. Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB . Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. J Immunol 2009; 182: 34–38.

    Article  CAS  PubMed  Google Scholar 

  28. Abelson AK, Delgado-Vega AM, Kozyrev SV, Sanchez E, Velazquez-Cruz R, Eriksson N et al. STAT4 associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Ann Rheum Dis 2008 (e-pub ahead of print).

  29. Namjou B, Sestak AL, Armstrong DL, Zidovetzki R, Kelly JA, Jacob N et al. High-density genotyping of STAT4 reveals multiple haplotypic associations with systemic lupus erythematosus in different racial groups. Arthritis Rheum 2009; 60: 1085–1095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Elder JT . Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis. Genes Immun 2009.

  31. Han S, Guthridge JM, Harley IT, Sestak AL, Kim-Howard X, Kaufman KM et al. Osteopontin and systemic lupus erythematosus association: a probable gene–gender interaction. PLoS ONE 2008; 3: e0001757.

    Article  PubMed  Google Scholar 

  32. Kariuki SN, Moore JG, Kirou KA, Crow MK, Utset TO, Niewold TB . Age- and gender-specific modulation of serum osteopontin and interferon-alpha by osteopontin genotype in systemic lupus erythematosus. Genes Immun 2009.

  33. Stetson DB, Ko JS, Heidmann T, Medzhitov R . Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 2008; 134: 587–598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sekine H, Ferreira RC, Pan-Hammarstrom Q, Graham RR, Ziemba B, de Vries SS et al. Role for Msh5 in the regulation of Ig class switch recombination. Proc Natl Acad Sci USA 2007; 104: 7193–7198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chung SA, Criswell LA . PTPN22: its role in SLE and autoimmunity. Autoimmunity 2007; 40: 582–590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Orru V, Tsai SJ, Rueda B, Fiorillo E, Stanford SM, Dasgupta J et al. A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum Mol Genet 2009; 18: 569–579.

    Article  CAS  PubMed  Google Scholar 

  37. Stuber E, Strober W . The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response. J Exp Med 1996; 183: 979–989.

    Article  CAS  PubMed  Google Scholar 

  38. Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002; 32: 666–669.

    Article  CAS  PubMed  Google Scholar 

  39. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG . Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: a meta-analysis. Lupus 2009; 18: 9–15.

    Article  CAS  PubMed  Google Scholar 

  40. Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR, Amos CI . Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. Am J Hum Genet 2008; 82: 100–112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Walport MJ . The Roche Rheumatology Prize Lecture. Complement deficiency and disease. Br J Rheumatol 1993; 32: 269–273.

    Article  CAS  PubMed  Google Scholar 

  42. Sullivan KE, Petri MA, Schmeckpeper BJ, McLean RH, Winkelstein JA . Prevalence of a mutation causing C2 deficiency in systemic lupus erythematosus. J Rheumatol 1994; 21: 1128–1133.

    CAS  PubMed  Google Scholar 

  43. Fielder AH, Walport MJ, Batchelor JR, Rynes RI, Black CM, Dodi IA et al. Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility. Br Med J (Clin Res Ed) 1983; 286: 425–428.

    Article  CAS  Google Scholar 

  44. Reveille JD, Arnett FC, Wilson RW, Bias WB, McLean RH . Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus. Immunogenetics 1985; 21: 299–311.

    Article  CAS  PubMed  Google Scholar 

  45. Morgan BP, Walport MJ . Complement deficiency and disease. Immunol Today 1991; 12: 301–306.

    Article  CAS  PubMed  Google Scholar 

  46. Botto M, Walport MJ . C1q, autoimmunity and apoptosis. Immunobiology 2002; 205: 395–406.

    Article  CAS  PubMed  Google Scholar 

  47. Harley JB . IL-7Ralpha and multiple sclerosis risk. Nat Genet 2007; 39: 1053–1054.

    Article  CAS  PubMed  Google Scholar 

  48. Edberg JC, Langefeld CD, Wu J, Moser KL, Kaufman KM, Kelly J et al. Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus. Arthritis Rheum 2002; 46: 2132–2140.

    Article  CAS  PubMed  Google Scholar 

  49. Salmon JE, Millard S, Schachter LA, Arnett FC, Ginzler EM, Gourley MF et al. Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans. J Clin Invest 1996; 97: 1348–1354.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. van der Pol W, van de Winkel JG . IgG receptor polymorphisms: risk factors for disease. Immunogenetics 1998; 48: 222–232.

    Article  CAS  PubMed  Google Scholar 

  51. Marnell L, Mold C, Du Clos TW . C-reactive protein: ligands, receptors and role in inflammation. Clin Immunol 2005; 117: 104–111.

    Article  CAS  PubMed  Google Scholar 

  52. Edberg JC, Wu J, Langefeld CD, Brown EE, Marion MC, McGwin Jr G et al. Genetic variation in the CRP promoter: association with systemic lupus erythematosus. Hum Mol Genet 2008; 17: 1147–1155.

    Article  CAS  PubMed  Google Scholar 

  53. Fanciulli M, Norsworthy PJ, Petretto E, Dong R, Harper L, Kamesh L et al. FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity. Nat Genet 2007; 39: 721–723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Han S, Kim-Howard X, Deshmukh H, Kamatani Y, Viswanathan P, Guthridge JM et al. Evaluation of imputation-based association in and around the integrin-alpha-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE). Hum Mol Genet 2009; 18: 1171–1180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Scofield RH, Bruner GR, Namjou B, Kimberly RP, Ramsey-Goldman R, Petri M et al. Klinefelter's syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene–dose effect from the X chromosome. Arthritis Rheum 2008; 58: 2511–2517.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Webb R, Wren JD, Jeffries M, Kelly JA, Kaufman KM, Tang Y et al. Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus. Arthritis Rheum 2009; 60: 1076–1084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work has been supported by the NIH (AR043274, AI24717, AR62277, AR42460, AI31584, DE015223, RR015577, RR020143, AR48940 and AR049084), the Mary Kirkland Scholarship, the Barrett Scholarship Fund, the Alliance for Lupus Research and the US Department of Veterans Affairs.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K L Moser.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moser, K., Kelly, J., Lessard, C. et al. Recent insights into the genetic basis of systemic lupus erythematosus. Genes Immun 10, 373–379 (2009). https://doi.org/10.1038/gene.2009.39

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2009.39

Keywords

This article is cited by

Search

Quick links