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 Article
  • Published:

Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy

Nature Reviews Rheumatology volume 20, pages 635–648 (2024)Cite this article

Subjects

Abstract

Systemic lupus erythematosus (SLE) is a prime example of how the interplay between genetic and environmental factors can trigger systemic autoimmunity, particularly in young women. Although clinical disease can take years to manifest, risk is established by the unique genetic makeup of an individual. Genome-wide association studies have identified almost 200 SLE-associated risk loci, yet unravelling the functional effect of these loci remains a challenge. New analytic tools have enabled researchers to delve deeper, leveraging DNA sequencing and cell-specific and immune pathway analysis to elucidate the immunopathogenic mechanisms. Both common genetic variants and rare non-synonymous mutations can interact to increase SLE risk. Notably, variants strongly associated with SLE are often located in genome super-enhancers that regulate MHC class II gene expression. Additionally, the 3D conformations of DNA and RNA contribute to genome regulation and innate immune system activation. Improved therapies for SLE are urgently needed and current and future knowledge from genetic and genomic research should provide new tools to facilitate patient diagnosis, enhance the identification of therapeutic targets and optimize testing of agents.

Key points

  • Identification of both common and rare monogenic DNA sequence variants associated with systemic lupus erythematosus (SLE) have advanced understanding of critical immune pathways contributing to SLE pathogenesis.

  • Common genetic variants and rare non-synonymous mutations might synergize to augment the risk of developing SLE.

  • Genetic variants that confer a strong association with SLE risk map to critical genome super-enhancers that regulate the expression of MHC class II genes.

  • 3D conformations of DNA and RNA contribute to genome regulation and innate immune system activation.

  • Ancestry-specific genetic risk scores based on relevant immune system pathways might improve the assessment of the risk of SLE.

  • Consideration of patient-specific genetic variants in clinical trial design should increase the success of drug development programmes.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Molecular pathways in SLE informed by common, MHC and rare genetic variants.
Fig. 2: The MHC class II super-enhancer region and related SLE risk variants.
Fig. 3: Z-DNA formation and immune activation in SLE.
Fig. 4: Enhancing polygenic risk scores for better SLE prediction and management.

Similar content being viewed by others

References

  1. Crow, M. K. Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets. Ann. Rheum. Dis. 82, 999–1014 (2023).

    Article  CAS  PubMed  Google Scholar 

  2. Morand, E. F., Fernandez-Ruiz, R., Blazer, A. & Niewold, T. B. Advances in the management of systemic lupus erythematosus. BMJ 383, e073980 (2023).

    Article  PubMed  Google Scholar 

  3. Fasano, S., Milone, A., Nicoletti, G. F., Isenberg, D. A. & Ciccia, F. Precision medicine in systemic lupus erythematosus. Nat. Rev. Rheumatol. 19, 331–342 (2023).

    Article  CAS  PubMed  Google Scholar 

  4. Vinuesa, C. G., Shen, N. & Ware, T. Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants. Nat. Rev. Nephrol. 19, 558–572 (2023).

    Article  CAS  PubMed  Google Scholar 

  5. Demkova, K., Morris, D. L. & Vyse, T. J. Genetics of SLE: does this explain susceptibility and severity across racial groups? Rheumatology 62, i15–i21 (2023).

    Article  PubMed  Google Scholar 

  6. Ghodke-Puranik, Y. & Niewold, T. B. Immunogenetics of systemic lupus erythematosus: a comprehensive review. J. Autoimmun. 64, 125–136 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stankey, C. T. & Lee, J. C. Translating non-coding genetic associations into a better understanding of immune-mediated disease. Dis. Model. Mech. 16, dmm049790 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chen, L. et al. Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity. Hum. Mol. Genet. 29, 1745–1756 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Langefeld, C. D. et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat. Commun. 8, 16021 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. International Consortium for Systemic Lupus Erythematosus Genetics et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

    Article  Google Scholar 

  11. Cunninghame Graham, D. S. et al. Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet. 7, e1002341 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Guga, S., Wang, Y., Graham, D. C. & Vyse, T. J. A review of genetic risk in systemic lupus erythematosus. Expert. Rev. Clin. Immunol. 19, 1247–1258 (2023).

    Article  CAS  PubMed  Google Scholar 

  13. Chen, L., Morris, D. L. & Vyse, T. J. Genetic advances in systemic lupus erythematosus: an update. Curr. Opin. Rheumatol. 29, 423–433 (2017).

    Article  PubMed  Google Scholar 

  14. Ghodke-Puranik, Y. et al. Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen. Cytokine 132, 154631 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Kariuki, S. N. et al. Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus. Genes. Immun. 16, 15–23 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Han, J. W. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Okada, Y. et al. A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese. PLoS Genet. 8, e1002455 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alarcon-Riquelme, M. E. et al. Genome-wide association study in an Amerindian ancestry population reveals novel systemic lupus erythematosus risk loci and the role of European admixture. Arthritis Rheumatol. 68, 932–943 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Morris, D. L. et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat. Genet. 48, 940–946 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rose, A. M. & Bell, L. C. Epistasis and immunity: the role of genetic interactions in autoimmune diseases. Immunology 137, 131–138 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ellinghaus, D. et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat. Genet. 48, 510–518 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Farh, K. K. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Scharer, C. D. et al. Epigenetic programming underpins B cell dysfunction in human SLE. Nat. Immunol. 20, 1071–1082 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Aune, T. M. et al. Expression of long non-coding RNAs in autoimmunity and linkage to enhancer function and autoimmune disease risk genetic variants. J. Autoimmun. 81, 99–109 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Almlof, J. C. et al. Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus. Hum. Genet. 138, 141–150 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Charras, A. et al. Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE. Rheumatology 62, SI210–SI225 (2023).

    Article  PubMed  Google Scholar 

  28. Dasdemir, S. et al. Genetic screening of early-onset patients with systemic lupus erythematosus by a targeted next-generation sequencing gene panel. Lupus 31, 330–337 (2022).

    Article  CAS  PubMed  Google Scholar 

  29. Delgado-Vega, A. M. et al. Whole exome sequencing of patients from multicase families with systemic lupus erythematosus identifies multiple rare variants. Sci. Rep. 8, 8775 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ellyard, J. I. et al. Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by whole-exome sequencing. Arthritis Rheumatol. 66, 3382–3386 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Jiang, S. H. et al. Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nat. Commun. 10, 2201 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lea-Henry, T. N. et al. Increased burden of rare variants in genes of the endosomal Toll-like receptor pathway in patients with systemic lupus erythematosus. Lupus 30, 1756–1763 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, Y. F. et al. Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups. Nat. Commun. 12, 772 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Harley, I. T. W. & Sawalha, A. H. Systemic lupus erythematosus as a genetic disease. Clin. Immunol. 236, 108953 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sandling, J. K. et al. Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing. Ann. Rheum. Dis. 80, 109–117 (2021).

    Article  CAS  PubMed  Google Scholar 

  36. Owen, K. A. et al. Analysis of trans-ancestral SLE risk loci identifies unique biologic networks and drug targets in African and European Ancestries. Am. J. Hum. Genet. 107, 864–881 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Crow, M. K. Advances in lupus therapeutics: achieving sustained control of the type I interferon pathway. Curr. Opin. Pharmacol. 67, 102291 (2022).

    Article  CAS  PubMed  Google Scholar 

  38. Raj, P. et al. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. Elife 5, e12089 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Alperin, J. M., Ortiz-Fernandez, L. & Sawalha, A. H. Monogenic lupus: a developing paradigm of disease. Front. Immunol. 9, 2496 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sullivan, K. E., Petri, M. A., Schmeckpeper, B. J., McLean, R. H. & Winkelstein, J. A. Prevalence of a mutation causing C2 deficiency in systemic lupus erythematosus. J. Rheumatol. 21, 1128–1133 (1994).

    CAS  PubMed  Google Scholar 

  41. Slingsby, J. H. et al. Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum. 39, 663–670 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Brown, G. J. et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 605, 349–356 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wolf, C. et al. UNC93B1 variants underlie TLR7-dependent autoimmunity. Sci. Immunol. 9, eadi9769 (2024).

    Article  CAS  PubMed  Google Scholar 

  44. Al-Azab, M. et al. Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus. Nat. Immunol. 25, 969–980 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. David, C. et al. Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus. J. Exp. Med. 221, e20232066 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Rael, V. et al. Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans. J. Exp. Med. 221, e20232005 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Mishra, H. et al. Disrupted degradative sorting of TLR7 is associated with human lupus. Sci. Immunol. 9, eadi9575 (2024).

    Article  CAS  PubMed  Google Scholar 

  48. Lee-Kirsch, M. A. et al. Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39, 1065–1067 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Natsumoto, B. et al. Functional evaluation of rare OASL variants by analysis of SLE patient-derived iPSCs. J. Autoimmun. 139, 103085 (2023).

    Article  CAS  PubMed  Google Scholar 

  50. Van Eyck, L. et al. Brief Report: IFIH1 mutation causes systemic lupus erythematosus with selective IgA deficiency. Arthritis Rheumatol. 67, 1592–1597 (2015).

    Article  PubMed  Google Scholar 

  51. Crow, Y. J. et al. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. Am. J. Med. Genet. A 167A, 296–312 (2015).

    Article  PubMed  Google Scholar 

  52. Al-Mayouf, S. M. et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat. Genet. 43, 1186–1188 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Coke, L. N. et al. Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus. Ann. Rheum. Dis. 80, 782–787 (2021).

    Article  CAS  PubMed  Google Scholar 

  54. Zhao, J. et al. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat. Genet. 49, 433–437 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schnappauf, O. et al. Homozygous variant p. Arg90His in NCF1 is associated with early-onset Interferonopathy: a case report. Pediatr. Rheumatol. Online J. 19, 54 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Linge, P. et al. NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus. Ann. Rheum. Dis. 79, 254–261 (2020).

    Article  CAS  PubMed  Google Scholar 

  57. Olsson, L. M. et al. A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus. Ann. Rheum. Dis. 76, 1607–1613 (2017).

    Article  CAS  PubMed  Google Scholar 

  58. He, Y. et al. P2RY8 variants in lupus patients uncover a role for the receptor in immunological tolerance. J. Exp. Med. 219, e20211004 (2022).

    Article  CAS  PubMed  Google Scholar 

  59. Zhang, Y. et al. Rare SH2B3 coding variants in lupus patients impair B cell tolerance and predispose to autoimmunity. J. Exp. Med 221, e20211080 (2024).

    Article  Google Scholar 

  60. Viel, K. et al. Shared and distinct interactions of type 1 and type 2 Epstein-Barr Nuclear Antigen 2 with the human genome. BMC Genomics 25, 273 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Qiu, Y. et al. 3D genome organization and epigenetic regulation in autoimmune diseases. Front. Immunol. 14, 1196123 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ray, J. P. et al. Prioritizing disease and trait causal variants at the TNFAIP3 locus using functional and genomic features. Nat. Commun. 11, 1237 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sokhi, U. K. et al. Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models. Nat. Commun. 9, 658 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Pasula, S. et al. Role of systemic lupus erythematosus risk variants with opposing functional effects as a driver of hypomorphic expression of TNIP1 and other genes within a three-dimensional chromatin network. Arthritis Rheumatol. 72, 780–790 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pasula, S. et al. Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3. Front. Genet. 13, 1011965 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hou, G. et al. SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression. Nat. Commun. 12, 135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kobayashi, T. et al. The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity 41, 375–388 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Chen, X. et al. Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling. Nat. Commun. 14, 6627 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hou, G. et al. Integrative functional genomics identifies systemic lupus erythematosus causal genetic variant in the IRF5 risk locus. Arthritis Rheumatol. 75, 574–585 (2023).

    Article  CAS  PubMed  Google Scholar 

  70. Zhou, Z. et al. TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I-like receptor-mediated innate immune response. Proc. Natl Acad. Sci. USA 111, E245–E254 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Hoffpauir, C. T. et al. TRIM14 is a key regulator of the type I IFN response during mycobacterium tuberculosis infection. J. Immunol. 205, 153–167 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lu, X. et al. Global discovery of lupus genetic risk variant allelic enhancer activity. Nat. Commun. 12, 1611 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fu, Y. et al. Massively parallel reporter assay confirms regulatory potential of hQTLs and reveals important variants in lupus and other autoimmune diseases. HGG Adv. 5, 100279 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Barcellos, L. F. et al. High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. PLoS Genet. 5, e1000696 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Shiina, T. & Kulski, J. K. HLA genetics for the human diseases. Adv. Exp. Med. Biol. 1444, 237–258 (2024).

    Article  PubMed  Google Scholar 

  76. Whitney, A. R. et al. Individuality and variation in gene expression patterns in human blood. Proc. Natl Acad. Sci. USA 100, 1896–1901 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Candore, G. et al. In vitro cytokine production by HLA-B8,DR3 positive subjects. Autoimmunity 18, 121–132 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Price, P. et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol. Rev. 167, 257–274 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Traherne, J. A. et al. Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history. PLoS Genet. 2, e9 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  80. McDevitt, H. O., Wraith, D. C., Smilek, D. E., Lundberg, A. S. & Steinman, L. Evolution, function, and utilization of major histocompatibility complex polymorphism in autoimmune disease. Cold Spring Harb. Symp. Quant. Biol. 54 Pt 2, 853–857 (1989).

    Article  CAS  PubMed  Google Scholar 

  81. Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).

    Article  CAS  PubMed  Google Scholar 

  82. Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Molineros, J. E. et al. Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians. PLoS Genet. 15, e1008092 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Xu, R. et al. Association analysis of the MHC in lupus nephritis. J. Am. Soc. Nephrol. 28, 3383–3394 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Morris, D. L. et al. MHC associations with clinical and autoantibody manifestations in European SLE. Genes. Immun. 15, 210–217 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Majumder, P., Gomez, J. A. & Boss, J. M. The human major histocompatibility complex class II HLA-DRB1 and HLA-DQA1 genes are separated by a CTCF-binding enhancer-blocking element. J. Biol. Chem. 281, 18435–18443 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Majumder, P., Gomez, J. A., Chadwick, B. P. & Boss, J. M. The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions. J. Exp. Med. 205, 785–798 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Majumder, P. et al. A super enhancer controls expression and chromatin architecture within the MHC class II locus. J. Exp. Med. 217, e20190668 (2020).

    Article  PubMed  Google Scholar 

  89. Cavalli, G. et al. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo. Proc. Natl Acad. Sci. USA 113, 1363–1368 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Kachru, R. B., Sequeira, W., Mittal, K. K., Siegel, M. E. & Telischi, M. A significant increase of HLA-DR3 and DR2 in systemic lupus erythematosus among Blacks. J. Rheumatol. 11, 471–474 (1984).

    CAS  PubMed  Google Scholar 

  91. Hanscombe, K. B. et al. Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. Hum. Mol. Genet. 27, 3813–3824 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Pelikan, R. C. et al. Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks. Nat. Commun. 9, 2905 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Ota, M. et al. Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases. Cell 184, 3006–3021 e3017 (2021).

    Article  CAS  PubMed  Google Scholar 

  94. Ghodke-Puranik, Y. et al. Single-cell expression quantitative trait loci (eQTL) analysis of SLE-risk loci in lupus patient monocytes. Arthritis Res. Ther. 23, 290 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kang, J. B. et al. Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution. Nat. Genet. 55, 2255–2268 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gupta, A. et al. Dynamic regulatory elements in single-cell multimodal data implicate key immune cell states enriched for autoimmune disease heritability. Nat. Genet. 55, 2200–2210 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mostafavi, H., Spence, J. P., Naqvi, S. & Pritchard, J. K. Systematic differences in discovery of genetic effects on gene expression and complex traits. Nat. Genet. 55, 1866–1875 (2023).

    Article  CAS  PubMed  Google Scholar 

  98. Zeng, Y. et al. DNA methylation modulated genetic variant effect on gene transcriptional regulation. Genome Biol. 24, 285 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Coss, S. L. et al. The complement system and human autoimmune diseases. J. Autoimmun. 137, 102979 (2023).

    Article  CAS  PubMed  Google Scholar 

  100. Yang, Y. et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am. J. Hum. Genet. 80, 1037–1054 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lundtoft, C. et al. Complement C4 copy number variation is linked to SSA/Ro and SSB/La autoantibodies in systemic inflammatory autoimmune diseases. Arthritis Rheumatol. 74, 1440–1450 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhou, T. et al. Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery. Nat. Commun. 13, 1855 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang, Y., Zhang, X., Dai, H. Q., Hu, H. & Alt, F. W. The role of chromatin loop extrusion in antibody diversification. Nat. Rev. Immunol. 22, 550–566 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Barajas-Mora, E. M. & Feeney, A. J. Enhancers within the Ig V gene region orchestrate chromatin topology and regulate V gene rearrangement frequency to shape the B cell receptor repertoire specificities. J. Immunol. 211, 1613–1622 (2023).

    Article  CAS  PubMed  Google Scholar 

  105. Hu, Y. et al. Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS. Cell 186, 5269–5289 e5222 (2023).

    Article  CAS  PubMed  Google Scholar 

  106. Vyse, T. J. & Cunninghame Graham, D. S. Trans-ancestral fine-mapping and epigenetic annotation as tools to delineate functionally relevant risk alleles at IKZF1 and IKZF3 in systemic lupus erythematosus. Int. J. Mol. Sci. 21, 8383 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhao, M. et al. 3D genome alterations in T cells associated with disease activity of systemic lupus erythematosus. Ann. Rheum. Dis. 82, 226–234 (2023).

    Article  CAS  PubMed  Google Scholar 

  108. Pisetsky, D. S. & Herbert, A. The role of DNA in the pathogenesis of SLE: DNA as a molecular chameleon. Ann. Rheum. Dis. 83, 830–837 (2024).

    Article  PubMed  Google Scholar 

  109. Krall, J. B., Nichols, P. J., Henen, M. A., Vicens, Q. & Vogeli, B. Structure and formation of Z-DNA and Z-RNA. Molecules 28, 843 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhao, C. et al. Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity. Immunity 56, 2508–2522 e2506 (2023).

    Article  CAS  PubMed  Google Scholar 

  111. Thomas, T. J. & Thomas, T. Polyamine-induced Z-DNA conformation in plasmids containing (dA-dC)n.(dG-dT)n inserts and increased binding of lupus autoantibodies to the Z-DNA form of plasmids. Biochem. J. 298, 485–491 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Klein, B. et al. Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity. Preprint at bioRxiv https://doi.org/10.1101/2024.01.23.576771 (2024).

  113. Xu, L. et al. Loss-of-function variants in SAT1 cause X-linked childhood-onset systemic lupus erythematosus. Ann. Rheum. Dis. 81, 1712–1721 (2022).

    Article  CAS  PubMed  Google Scholar 

  114. Herbert, A. Z-DNA and Z-RNA in human disease. Commun. Biol. 2, 7 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Tang, Q. et al. Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses. Immunity 54, 1961–1975 e1965 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Jiao, H. et al. ADAR1 averts fatal type I interferon induction by ZBP1. Nature 607, 776–783 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hubbard, N. W. et al. ADAR1 mutation causes ZBP1-dependent immunopathology. Nature 607, 769–775 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. de Reuver, R. et al. ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. Nature 607, 784–789 (2022).

    Article  PubMed  Google Scholar 

  119. Ramesh, N. & Brahmachari, S. K. Structural alteration from non-B to B-form could reflect DNase I hypersensitivity. J. Biomol. Struct. Dyn. 6, 899–906 (1989).

    Article  CAS  PubMed  Google Scholar 

  120. Herbert, A. Flipons and small RNAs accentuate the asymmetries of pervasive transcription by the reset and sequence-specific microcoding of promoter conformation. J. Biol. Chem. 299, 105140 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Spencer, D. M., Svenungsson, E., Gunnarsson, I., Caricchio, R. & Pisetsky, D. S. The expression of antibodies to Z-DNA in the blood of patients with systemic lupus erythematosus: relationship to autoantibodies to B-DNA. Clin. Immunol. 255, 109763 (2023).

    Article  CAS  PubMed  Google Scholar 

  122. Webber, D. et al. Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE. Rheumatology 59, 90–98 (2020).

    Article  PubMed  Google Scholar 

  123. Barnado, A. et al. Phenotype risk score but not genetic risk score aids in identifying individuals with systemic lupus erythematosus in the electronic health record. Arthritis Rheumatol. 75, 1532–1541 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Lennon, N. J. et al. Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations. Nat. Med. 30, 480–487 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Knevel, R. et al. Using genetics to prioritize diagnoses for rheumatology outpatients with inflammatory arthritis. Sci. Transl. Med. 12, eaay1548 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Reid, S. et al. High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus. Ann. Rheum. Dis. 79, 363–369 (2020).

    Article  CAS  PubMed  Google Scholar 

  127. Shin, J. M. et al. Clinical and genetic risk factors associated with the presence of lupus nephritis. J. Rheum. Dis. 28, 150–158 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Dominguez, D. et al. Relationship between genetic risk and age of diagnosis in systemic lupus erythematosus. J. Rheumatol. 48, 852–858 (2021).

    Article  CAS  PubMed  Google Scholar 

  129. Hedenstedt, A. et al. B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus. Lupus Sci. Med. 10, e000926 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Chung, C. P. et al. APOL1 and the risk of adverse renal outcomes in patients of African ancestry with systemic lupus erythematosus. Lupus 32, 763–770 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Prive, F. et al. Portability of 245 polygenic scores when derived from the UK Biobank and applied to 9 ancestry groups from the same cohort. Am. J. Hum. Genet. 109, 12–23 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Wang, Y., Tsuo, K., Kanai, M., Neale, B. M. & Martin, A. R. Challenges and opportunities for developing more generalizable polygenic risk scores. Annu. Rev. Biomed. Data Sci. 5, 293–320 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Collister, J. A., Liu, X. & Clifton, L. Calculating polygenic risk scores (PRS) in UK biobank: a practical guide for epidemiologists. Front. Genet. 13, 818574 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ochoa, D. et al. Human genetics evidence supports two-thirds of the 2021 FDA-approved drugs. Nat. Rev. Drug. Discov. 21, 551 (2022).

    Article  CAS  PubMed  Google Scholar 

  135. Morand, E. et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase II, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 75, 242–252 (2023).

    Article  CAS  PubMed  Google Scholar 

  136. Ban, T. et al. Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease. Nat. Commun. 12, 4379 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Boeszoermenyi, A. et al. A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity. Nat. Commun. 14, 6626 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Furie, R. et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 69, 376–386 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Morand, E. F. et al. Trial of anifrolumab in active systemic lupus erythematosus. N. Engl. J. Med. 382, 211–221 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Felten, R., Scher, F., Sagez, F., Chasset, F. & Arnaud, L. Spotlight on anifrolumab and its potential for the treatment of moderate-to-severe systemic lupus erythematosus: evidence to date. Drug. Des. Devel Ther. 13, 1535–1543 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Schett, G., Mielenz, D., Nagy, G. & Kronke, G. B-cell depletion in autoimmune diseases. Ann. Rheum. Dis. 11, 1126421 (2024).

    Google Scholar 

  142. Garantziotis, P. et al. Molecular taxonomy of systemic lupus erythematosus through data-driven patient stratification: molecular endotypes and cluster-tailored drugs. Front. Immunol. 13, 860726 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Toro-Dominguez, D., Carmona-Saez, P. & Alarcon-Riquelme, M. E. Support for phosphoinositol 3 kinase and mTOR inhibitors as treatment for lupus using in-silico drug-repurposing analysis. Arthritis Res. Ther. 19, 54 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Wang, Y. F. et al. Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning. Ann. Rheum. Dis. 77, 1078–1084 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Toro-Dominguez, D. et al. Differential treatments based on drug-induced gene expression signatures and longitudinal systemic lupus erythematosus stratification. Sci. Rep. 9, 15502 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Hubbard, E. L. et al. Analysis of gene expression from systemic lupus erythematosus synovium reveals myeloid cell-driven pathogenesis of lupus arthritis. Sci. Rep. 10, 17361 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Nelson, M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015).

    Article  CAS  PubMed  Google Scholar 

  148. Allen, M. E., Rus, V. & Szeto, G. L. Leveraging heterogeneity in systemic lupus erythematosus for new therapies. Trends Mol. Med. 27, 152–171 (2021).

    Article  CAS  PubMed  Google Scholar 

  149. Hurle, M. R., Nelson, M. R., Agarwal, P. & Cardon, L. R. Impact of genetically supported target selection on R&D productivity. Nat. Rev. Drug. Discov. 15, 596–597 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. King, E. A., Davis, J. W. & Degner, J. F. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLoS Genet. 15, e1008489 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Vital, E. M. et al. Anifrolumab efficacy and safety by type I interferon gene signature and clinical subgroups in patients with SLE: post hoc analysis of pooled data from two phase III trials. Ann. Rheum. Dis. 81, 951–961 (2022).

    Article  CAS  PubMed  Google Scholar 

  152. Merrill, J. T. et al. Phase 2 trial of iberdomide in systemic lupus erythematosus. N. Engl. J. Med. 386, 1034–1045 (2022).

    Article  CAS  PubMed  Google Scholar 

  153. Fanouriakis, A. et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann. Rheum. Dis. 83, 15–29 (2023).

    Article  Google Scholar 

  154. Franklyn, K. et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann. Rheum. Dis. 75, 1615–1621 (2016).

    Article  CAS  PubMed  Google Scholar 

  155. Nakano, M. et al. Distinct transcriptome architectures underlying lupus establishment and exacerbation. Cell 185, 3375–3389 e3321 (2022).

    Article  CAS  PubMed  Google Scholar 

  156. Yu, H., Nagafuchi, Y. & Fujio, K. Clinical and immunological biomarkers for systemic lupus erythematosus. Biomolecules 11, 928 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Arazi, A. et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat. Immunol. 20, 902–914 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jourde-Chiche, N. et al. Modular transcriptional repertoire analyses identify a blood neutrophil signature as a candidate biomarker for lupus nephritis. Rheumatology 56, 477–487 (2017).

    CAS  PubMed  Google Scholar 

  159. Banchereau, R. et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165, 551–565 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Fava, A. et al. Urine proteomics and renal single-cell transcriptomics implicate interleukin-16 in lupus nephritis. Arthritis Rheumatol. 74, 829–839 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Wang, T. Y. et al. Identification of regulatory modules that stratify lupus disease mechanism through integrating multi-omics data. Mol. Ther. Nucleic Acids 19, 318–329 (2020).

    Article  CAS  PubMed  Google Scholar 

  162. Der, E. et al. Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat. Immunol. 20, 915–927 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Nehar-Belaid, D. et al. Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nat. Immunol. 21, 1094–1106 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Nassar, L. R. et al. The UCSC genome browser database: 2023 update. Nucleic Acids Res. 51, D1188–DD195 (2023).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of M.K.C. is supported by the Mary K. Crow Chair in Immunology and Inflammation Research.

Author information

Authors and Affiliations

  1. Mary Kirkland Center for Lupus Research, Hospital for Special Surgery and Weill Cornell Medicine, New York, NY, USA

    Yogita Ghodke-Puranik, Mikhail Olferiev & Mary K. Crow

Authors
  1. Yogita Ghodke-Puranik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mikhail Olferiev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary K. Crow
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. M.K.C. and Y.G.-P. wrote the article.

Corresponding author

Correspondence to Mary K. Crow.

Ethics declarations

Competing interests

M.K.C. has served as a consultant for Aboleris, AbelZeta, AMPEL Biosolutions, Astra Zeneca, BMS, GSK, Lilly, Novartis and Takeda, and holds stocks in Amgen, Johnson and Johnson and Regeneron. Y.G.-P. and M.O. declare no competing interests.

Peer review

Peer review information

Nature Reviews Rheumatology thanks Leah Kottyan; Linda Hiraki; Marta Alarcón-Riquelme, who co-reviewed with Ruth Domínguez Rodríguez; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ghodke-Puranik, Y., Olferiev, M. & Crow, M.K. Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy. Nat Rev Rheumatol 20, 635–648 (2024). https://doi.org/10.1038/s41584-024-01152-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-024-01152-2

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing