Rare Variants in Systemic Lupus Erythematosus: From Monogenic to Polygenic Disease

Main Article Content

Marta E. Alarcón-Riquelme Ruth D. Rodríguez


The clinical and genotypic characterization of autoimmune diseases, including systemic lupus erythematosus (SLE), has made great strides recently as a result of tremendous advancements in gene sequencing technologies. Systemic lupus erythematosus is a complex multisystem disease characterized by high clinical variability due to abnormalities in both the innate and adaptive immune systems. Several genetic variants as well as environmental and hormonal factors have been identified, but the etiology of lupus is not fully understood yet. The ability of genome-wide association studies to scan thousands of individuals has enabled researchers to associate thousands of common variants to lupus. Common polymorphisms may jointly predispose to lupus, but their individual impact on the disease is minimal. It's becoming progressively more evident that rare mutations have a far higher influence. The role of rare variation in lupus has been the subject of intense research. Several approaches including genotyped-based follow-up of the variants in families, hierarchical screening, and imputation, have been applied to elucidate their functional involvement. Nevertheless, due to their rarity and the absence of standardized methodology, rare variants are still challenging to study.

Most lupus patients present a polygenic form of the disease, which is defined by the complex interplay between genetic and environmental factors. Still, certain lupus patients and patients with lupus-like phenotypes might be affected by monogenic lupus, a group of disorders largely caused by individual gene mutation abnormalities. Although monogenic lupus is rare, it has been associated with a sizable number of genes in a range of pathways, mostly resulting in early-onset phenotypes. The study of rare variants causing monogenic lupus has resulted in incredibly useful breakthroughs in our understanding of the function of rare variants in the disease, nonetheless further research is still required.

Keywords: Systemic Erythematosus Lupus, SLE, monogenic lupus, polygenic lupus, rare variants

Article Details

How to Cite
ALARCÓN-RIQUELME, Marta E.; RODRÍGUEZ, Ruth D.. Rare Variants in Systemic Lupus Erythematosus: From Monogenic to Polygenic Disease. Medical Research Archives, [S.l.], v. 11, n. 10, oct. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4363>. Date accessed: 11 dec. 2023. doi: https://doi.org/10.18103/mra.v11i10.4363.
Review Articles


1. Pan L, Lu MP, Wang JH, Xu M, Yang SR. Immunological pathogenesis and treatment of systemic lupus erythematosus. World J Pediatr. 2020;16(1):19-30. doi:10.1007/s12519-019-00229-3
2. Fike AJ, Elcheva I, Rahman ZSM. The Post-GWAS Era: How to Validate the Contribution of Gene Variants in Lupus. Curr Rheumatol Rep. 2019;21(1):3. doi:10.1007/s11926-019-0801-5
3. Schwartzman-Morris J, Putterman C. Gender Differences in the Pathogenesis and Outcome of Lupus and of Lupus Nephritis. Clin Dev Immunol. 2012;2012:e604892. doi:10.1155/2012/604892
4. Owen KA, Price A, Ainsworth H, 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. 2020;107(5):864-881. doi:10.1016/j.ajhg.2020.09.007
5. Sánchez E, Rasmussen A, Riba L, et al. Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations. Arthritis Rheum. 2012;64(11):3687-3694. doi:10.1002/art.34650
6. Kuo L, Chang BG. The affecting factors of circular economy information and its impact on corporate economic sustainability-Evidence from China. Sustain Prod Consum. 2021;27:986-997. doi:10.1016/j.spc.2021.02.014
7. Selmi C, Lu Q, Humble MC. Heritability versus the role of the environment in autoimmunity. J Autoimmun. 2012;39(4):249-252. doi:10.1016/j.jaut.2012.07.011
8. Langefeld CD, Ainsworth HC, Graham DSC, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017;8(1):16021. doi:10.1038/ncomms16021
9. Ortíz-Fernández L, Martín J, Alarcón-Riquelme ME. A Summary on the Genetics of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, and Sjögren’s Syndrome. Clin Rev Allergy Immunol. 2023;64(3):392-411. doi:10.1007/s12016-022-08951-z
10. Almlöf JC, Nystedt S, Leonard D, et al. Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus. Hum Genet. 2019;138(2):141-150. doi:10.1007/s00439-018-01966-7
11. Jiang SH, Stanley M, Vinuesa CG. Rare genetic variants in systemic autoimmunity. Immunol Cell Biol. 2020;98(6):490-499. doi:10.1111/imcb.12339
12. Martínez-Bueno M, Alarcón-Riquelme ME. Exploring Impact of Rare Variation in Systemic Lupus Erythematosus by a Genome Wide Imputation Approach. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.00258
13. Saint Pierre A, Génin E. How important are rare variants in common disease? Brief Funct Genomics. 2014;13(5):353-361. doi:10.1093/bfgp/elu025
14. Alperin JM, Ortiz-Fernández L, Sawalha AH. Monogenic Lupus: A Developing Paradigm of Disease. Front Immunol. 2018;9:2496. doi:10.3389/fimmu.2018.02496
15. d’Angelo DM, Di Filippo P, Breda L, Chiarelli F. Type I Interferonopathies in Children: An Overview. Front Pediatr. 2021;9. Accessed June 9, 2023. https://www.frontiersin.org/articles/10.3389/fped.2021.631329
16. Demirkaya E, Sahin S, Romano M, Zhou Q, Aksentijevich I. New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond. J Clin Med. 2020;9(3):712. doi:10.3390/jcm9030712
17. Günther C, Kind B, Reijns MAM, et al. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest. 2015;125(1):413-424. doi:10.1172/JCI78001
18. Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement System Part II: Role in Immunity. Front Immunol. 2015;6. Accessed May 26, 2023. https://www.frontiersin.org/articles/10.3389/fimmu.2015.00257
19. Ostrycharz E, Hukowska-Szematowicz B. New Insights into the Role of the Complement System in Human Viral Diseases. Biomolecules. 2022;12(2):226. doi:10.3390/biom12020226
20. Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343(1):227-235. doi:10.1007/s00441-010-1034-0
21. Macedo ACL, Isaac L. Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway. Front Immunol. 2016;7:55. doi:10.3389/fimmu.2016.00055
22. Truedsson L, Bengtsson AA, Sturfelt G. Complement deficiencies and systemic lupus erythematosus. Autoimmunity. 2007;40(8):560-566. doi:10.1080/08916930701510673
23. Xie CB, Jane-Wit D, Pober JS. Complement Membrane Attack Complex: New Roles, Mechanisms of Action, and Therapeutic Targets. Am J Pathol. 2020;190(6):1138-1150. doi:10.1016/j.ajpath.2020.02.006
24. Cho H. Complement regulation: physiology and disease relevance. Korean J Pediatr. 2015;58(7):239-244. doi:10.3345/kjp.2015.58.7.239
25. Kim DD, Song WC. Membrane complement regulatory proteins. Clin Immunol Orlando Fla. 2006;118(2-3):127-136. doi:10.1016/j.clim.2005.10.014
26. Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9(10):729-740. doi:10.1038/nri2620
27. Fernandez-Ruiz R, Belmont HM. The role of anticomplement therapy in lupus nephritis. Transl Res. 2022;245:1-17. doi:10.1016/j.trsl.2022.02.001
28. Fraser DA, Pisalyaput K, Tenner AJ. C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem. 2010;112(3):733-743. doi:10.1111/j.1471-4159.2009.06494.x
29. Costa-Reis P, Sullivan KE. Monogenic lupus: it’s all new! Curr Opin Immunol. 2017;49:87-95. doi:10.1016/j.coi.2017.10.008
30. Lintner KE, Wu YL, Yang Y, et al. Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Front Immunol. 2016;7. Accessed May 26, 2023. https://www.frontiersin.org/articles/10.3389/fimmu.2016.00036
31. Laich A, Patel H, Zarantonello A, Sim RB, Inal JM. C2 by-pass: Cross-talk between the complement classical and alternative pathways. Immunobiology. 2022;227(3):152225. doi:10.1016/j.imbio.2022.152225
32. Chen JY, Wu YL, Mok MY, et al. Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations. Arthritis Rheumatol Hoboken NJ. 2016;68(6):1442-1453. doi:10.1002/art.39589
33. Wu Z, Zhang S, Li P, Zhang F, Li Y. Association between complement 4 copy number variation and systemic lupus erythematosus: a meta-analysis. Clin Exp Med. 2020;20(4):627-634. doi:10.1007/s10238-020-00640-5
34. Yang Y, Chung EK, Wu YL, 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. 2007;80(6):1037-1054. doi:10.1086/518257
35. Tsokos GC, Lo MS, Reis PC, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716-730. doi:10.1038/nrrheum.2016.186
36. Capobianchi MR, Uleri E, Caglioti C, Dolei A. Type I IFN family members: Similarity, differences and interaction. Cytokine Growth Factor Rev. 2015;26(2):103-111. doi:10.1016/j.cytogfr.2014.10.011
37. Manry J, Laval G, Patin E, et al. Evolutionary genetic dissection of human interferons. J Exp Med. 2011;208(13):2747-2759. doi:10.1084/jem.20111680
38. McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A. Type I interferons in infectious disease. Nat Rev Immunol. 2015;15(2):87-103. doi:10.1038/nri3787
39. Brown GJ, Cañete PF, Wang H, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature. 2022;605(7909):349-356. doi:10.1038/s41586-022-04642-z
40. Arazi A, Rao DA, Berthier CC, et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol. 2019;20(7):902-914. doi:10.1038/s41590-019-0398-x
41. Banchereau R, Hong S, Cantarel B, et al. Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell. 2016;165(3):551-565. doi:10.1016/j.cell.2016.03.008
42. Billi AC, Ma F, Plazyo O, et al. Nonlesional lupus skin contributes to inflammatory education of myeloid cells and primes for cutaneous inflammation. Sci Transl Med. 2022;14(642):eabn2263. doi:10.1126/scitranslmed.abn2263
43. Dunlap GS, Billi AC, Xing X, et al. Single-cell transcriptomics reveals distinct effector profiles of infiltrating T cells in lupus skin and kidney. JCI Insight. 2022;7(8):e156341. doi:10.1172/jci.insight.156341
44. Fava A, Buyon J, Mohan C, et al. Integrated urine proteomics and renal single-cell genomics identify an IFN-γ response gradient in lupus nephritis. JCI Insight. 2020;5(12):e138345, 138345. doi:10.1172/jci.insight.138345
45. Guthridge JM, Lu R, Tran LTH, et al. Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study. EClinicalMedicine. 2020;20:100291. doi:10.1016/j.eclinm.2020.100291
46. Lindblom J, Toro-Domínguez D, Carnero-Montoro E, et al. Distinct gene dysregulation patterns herald precision medicine potentiality in systemic lupus erythematosus. J Autoimmun. 2023;136:103025. doi:10.1016/j.jaut.2023.103025
47. Nehar-Belaid D, Hong S, Marches R, et al. Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nat Immunol. 2020;21(9):1094-1106. doi:10.1038/s41590-020-0743-0
48. Perez RK, Gordon MG, Subramaniam M, et al. Single-cell RNA-seq reveals cell type–specific molecular and genetic associations to lupus. Science. 2022;376(6589):eabf1970. doi:10.1126/science.abf1970
49. Toro-Domínguez D, Martorell-Marugán J, Martinez-Bueno M, et al. Scoring personalized molecular portraits identify Systemic Lupus Erythematosus subtypes and predict individualized drug responses, symptomatology and disease progression. Brief Bioinform. 2022;23(5):bbac332. doi:10.1093/bib/bbac332
50. Chitrabamrung S, Rubin RL, Tan EM. Serum deoxyribonuclease I and clinical activity in systemic lupus erythematosus. Rheumatol Int. 1981;1(2):55-60. doi:10.1007/BF00541153
51. Lachmann PJ. An attempt to characterize the lupus erythematosus cell antigen. Immunology. 1961;4(2):153-163.
52. Martínez Valle F, Balada E, Ordi-Ros J, Vilardell-Tarres M. DNase 1 and systemic lupus erythematosus. Autoimmun Rev. 2008;7(5):359-363. doi:10.1016/j.autrev.2008.02.002
53. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG, Möröy T. Features of systemic lupus erythematosus in Dnase1-deficient mice. Nat Genet. 2000;25(2):177-181. doi:10.1038/76032
54. Yasutomo K, Horiuchi T, Kagami S, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet. 2001;28(4):313-314. doi:10.1038/91070
55. Bruschi M, Bonanni A, Petretto A, et al. Neutrophil Extracellular Traps (NETs) profiles in patients with incident SLE and lupus nephritis. J Rheumatol. 2020;47(3):377-386. doi:10.3899/jrheum.181232
56. Soni C, Reizis B. Self-DNA at the Epicenter of SLE: Immunogenic Forms, Regulation, and Effects. Front Immunol. 2019;10. Accessed June 12, 2023. https://www.frontiersin.org/articles/10.3389/fimmu.2019.01601
57. Pisetsky DS. Anti-DNA antibodies — quintessential biomarkers of SLE. Nat Rev Rheumatol. 2016;12(2):102-110. doi:10.1038/nrrheum.2015.151
58. Rodero MP, Decalf J, Bondet V, et al. Detection of interferon alpha protein reveals differential levels and cellular sources in disease. J Exp Med. 2017;214(5):1547-1555. doi:10.1084/jem.20161451
59. Ramantani G, Kohlhase J, Hertzberg C, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis Rheum. 2010;62(5):1469-1477. doi:10.1002/art.27367
60. Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associated with mutations in TREX1. J Clin Immunol. 2015;35(3):235-243. doi:10.1007/s10875-015-0147-3
61. Lee-Kirsch MA, Gong M, Schulz H, et al. Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet. 2006;79(4):731-737. doi:10.1086/507848
62. Yamashiro K, Tanaka R, Li Y, Mikasa M, Hattori N. A TREX1 mutation causing cerebral vasculopathy in a patient with familial chilblain lupus. J Neurol. 2013;260(10):2653-2655. doi:10.1007/s00415-013-7084-y
63. Rehwinkel J, Maelfait J, Bridgeman A, et al. SAMHD1-dependent retroviral control and escape in mice. EMBO J. 2013;32(18):2454-2462. doi:10.1038/emboj.2013.163
64. Crow YJ, Chase DS, Lowenstein Schmidt 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. 2015;167(2):296-312. doi:10.1002/ajmg.a.36887
65. Roth SH, Danan-Gotthold M, Ben-Izhak M, et al. Increased RNA Editing May Provide a Source for Autoantigens in Systemic Lupus Erythematosus. Cell Rep. 2018;23(1):50-57. doi:10.1016/j.celrep.2018.03.036
66. Song B, Shiromoto Y, Minakuchi M, Nishikura K. The role of RNA editing enzyme ADAR1 in human disease. WIREs RNA. 2022;13(1):e1665. doi:10.1002/wrna.1665
67. Lo MS, Tsokos GC. Recent developments in systemic lupus erythematosus pathogenesis and applications for therapy. Curr Opin Rheumatol. 2018;30(2):222-228. doi:10.1097/BOR.0000000000000474
68. An J, Briggs TA, Dumax-Vorzet A, et al. Tartrate-Resistant Acid Phosphatase Deficiency in the Predisposition to Systemic Lupus Erythematosus. Arthritis Rheumatol Hoboken NJ. 2017;69(1):131-142. doi:10.1002/art.39810
69. Lausch E, Janecke A, Bros M, et al. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet. 2011;43(2):132-137. doi:10.1038/ng.749
70. Briggs TA, Rice GI, Daly S, et al. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet. 2011;43(2):127-131. doi:10.1038/ng.748
71. Crow YJ, Stetson DB. The type I interferonopathies: 10 years on. Nat Rev Immunol. 2022;22(8):471-483. doi:10.1038/s41577-021-00633-9
72. Yuan Y, Ma H, Ye Z, Jing W, Jiang Z. Interferon-stimulated gene 15 expression in systemic lupus erythematosus : Diagnostic value and association with lymphocytopenia. Z Rheumatol. 2018;77(3):256-262. doi:10.1007/s00393-017-0274-8
73. Lu D, Song J, Sun Y, et al. Mutations of deubiquitinase OTUD1 are associated with autoimmune disorders. J Autoimmun. 2018;94:156-165. doi:10.1016/j.jaut.2018.07.019
74. Salzer E, Santos-Valente E, Keller B, Warnatz K, Boztug K. Protein Kinase C δ: a Gatekeeper of Immune Homeostasis. J Clin Immunol. 2016;36(7):631-640. doi:10.1007/s10875-016-0323-0
75. Belot A, Kasher PR, Trotter EW, et al. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013;65(8):2161-2171. doi:10.1002/art.38008
76. Walter JE, Lo MS, Kis-Toth K, et al. Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. J Allergy Clin Immunol. 2015;135(1):272-273. doi:10.1016/j.jaci.2014.07.063
77. Omarjee O, Picard C, Frachette C, et al. Monogenic lupus: Dissecting heterogeneity. Autoimmun Rev. 2019;18(10):102361. doi:10.1016/j.autrev.2019.102361
78. Ishigaki K. Beyond GWAS: from simple associations to functional insights. Semin Immunopathol. 2022;44(1):3-14. doi:10.1007/s00281-021-00894-5
79. Klein RJ, Zeiss C, Chew EY, et al. Complement Factor H Polymorphism in Age-Related Macular Degeneration. Science. 2005;308(5720):385-389. doi:10.1126/science.1109557
80. Saurabh R, Fouodo CJK, König IR, Busch H, Wohlers I. A survey of genome-wide association studies, polygenic scores and UK Biobank highlights resources for autoimmune disease genetics. Front Immunol. 2022;13. Accessed June 15, 2023. https://www.frontiersin.org/articles/10.3389/fimmu.2022.972107
81. Kwon YC, Chun S, Kim K, Mak A. Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond. Cells. 2019;8(10):1180. doi:10.3390/cells8101180
82. Bentham J, Morris DL, Graham DSC, et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. 2015;47(12):1457-1464. doi:10.1038/ng.3434
83. Alarcón-Riquelme ME, Ziegler JT, Molineros J, 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 Hoboken NJ. 2016;68(4):932-943. doi:10.1002/art.39504
84. Oparina N, Martínez-Bueno M, Alarcón-Riquelme ME. An update on the genetics of systemic lupus erythematosus. Curr Opin Rheumatol. 2019;31(6):659. doi:10.1097/BOR.0000000000000654
85. Kottyan LC, Zoller EE, Bene J, et al. The IRF5–TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet. 2015;24(2):582-596. doi:10.1093/hmg/ddu455
86. Hou G, Zhou T, Xu N, et al. Integrative Functional Genomics Identifies Systemic Lupus Erythematosus Causal Genetic Variant in the IRF5 Risk Locus. Arthritis Rheumatol. 2023;75(4):574-585. doi:10.1002/art.42390
87. Jones SA, Cantsilieris S, Fan H, et al. Rare variants in non-coding regulatory regions of the genome that affect gene expression in systemic lupus erythematosus. Sci Rep. 2019;9(1):15433. doi:10.1038/s41598-019-51864-9
88. Morris DL, Sheng Y, Zhang Y, et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet. 2016;48(8):940-946. doi:10.1038/ng.3603
89. Sun C, Molineros JE, Looger LL, et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet. 2016;48(3):323-330. doi:10.1038/ng.3496
90. Yin X, Kim K, Suetsugu H, et al. Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus. Ann Rheum Dis. 2021;80(5):632-640. doi:10.1136/annrheumdis-2020-219209
91. Génin E. Missing heritability of complex diseases: case solved? Hum Genet. 2020;139(1):103-113. doi:10.1007/s00439-019-02034-4
92. Delgado-Vega AM, Martínez-Bueno M, Oparina NY, et al. Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants. Sci Rep. 2018;8(1):8775. doi:10.1038/s41598-018-26274-y
93. Souyris M, Cenac C, Azar P, et al. TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol. 2018;3(19):eaap8855. doi:10.1126/sciimmunol.aap8855
94. Harris VM, Koelsch KA, Kurien BT, et al. Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis. Front Immunol. 2019;10. Accessed June 18, 2023. https://www.frontiersin.org/articles/10.3389/fimmu.2019.02160