Current understanding of the genetic model of systemic sclerosis
A.S. Trofimova, M.A. Chernyavskaya, V.I. Mazurov, I.A. Leineman, E.A. Trofimov
ABSTRACT. Systemic sclerosis (SSc) is a rare systemic autoimmune disease of connective tissue characterized by a markedly heterogeneous clinical course and multiorgan involvement. The etiology of the disease is considered the result of a complex interaction between exogenous trigger factors and a genetic predisposition. Viral and bacterial infections, occupational hazards (exposure to silica dust, chemicals), and exposure to cold are discussed in the current literature as potential triggers. Along with studying these external factors, in recent years, scientists have focused on identifying new genetic markers for the development of SSc. An analysis of current data on the genetic basis of predisposition to SSс and the mechanisms of its development was conducted based on a review of literature data for the period from 2010 to 2026. A search for relevant sources was conducted in the international databases PubMed, Scopus, Web of Science, as well as in the Russian scientific electronic library eLibrary.ru.
For citation: Trofimova AS, Chernyavskaya MA, Mazurov VI, Leineman IA, Trofimov EA. Current understanding of the genetic model of systemic sclerosis. Therapy (Moscow). 2026;12(5S):116–123.
https://doi.org/10.18565/ therapy.2026.5-s5.116-123
Ключевые слова
systemic scleroderma
genetics
predisposition
polymorphism
HLA
Список литературы
1. Trofimova AS, Shokhin AA, Trofimov EA, Shostak MS. [Clinical case of systemic sclerosis in a male patient: Gender differences and possibilities of capillaroscopy. Sovremennaya revmatologiya = Modern Rheumatology Journal. 2024;18(1):84–89 (In Russ.)].
EDN: JPIBTM. https://doi.org/10.14412/1996-7012-2024-1-84-89
2. Mazurov VI, Gaidukova IZ, Belyaeva IB. [Clinical rheumatology. 3rd edition, revised and enlarged. A guide for doctors. Moscow: E-noto. 2021; 696 pp. (In Russ.)]. ISBN: 978-5-906023-26-1.
3. Gumkowska-Sroka O, Kotyla K, Kotyla P. Immunogenetics of systemic sclerosis. Genes (Basel). 2024;15(5):586.
PMID: 38790215. PMCID: PMC11121022. https://doi.org/10.3390/genes15050586
4. El-Halwagi A, Agarwal SK. Insights into the genetic landscape of systemic sclerosis. Best Pract Res Clin Rheumatol. 2024;38(4):101981.
PMID: 39068103. https://doi.org/10.1016/j.berh.2024.101981
5. Pattanaik D, Brown M, Postlethwaite BC, Postlethwaite AE. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6:272.
PMID: 26106387. PMCID: PMC4459100. https://doi.org/10.3389/fimmu.2015.00272
6. Bossini-Castillo L, Broen JC, Simeon CP, Beretta L, Vonk MC, Ortego-Centeno N, et al. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort. Ann Rheum Dis. 2011;70(4):638–41.
PMID: 21187296. https://doi.org/10.1136/ard.2010.141838. Erratum in: Ann Rheum Dis. 2011;70(8):1520
7. Ota Y, Kuwana M. Updates on genetics in systemic sclerosis. Inflamm Regen. 2021;41(1):17.
PMID: 34130729. PMCID: PMC8204536. https://doi.org/10.1186/s41232-021-00167-6
8. Reveille JD, Fischbach M, McNearney T, Friedman AW, Aguilar MB, Lisse J, et al.; GENISOS Study Group. Systemic sclerosis in 3 US ethnic groups: A comparison of clinical, sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum. 2001;30(5):332–46.
PMID: 11303306. https://doi.org/10.1053/sarh.2001.20268
9. Gilchrist FC, Bunn C, Foley PJ, Lympany PA, Black CM, Welsh KI, du Bois RM. Class II HLA associations with autoantibodies in scleroderma: A highly significant role for HLA-DP. Genes Immun. 2001;2(2):76–81.
PMID: 11393660. https://doi.org/10.1038/sj.gene.6363734
10. Arnett FC, Gourh P, Shete S, Ahn CW, Honey RE, Agarwal SK, et al. Major Histocompatibility Complex (MHC) class II alleles, haplotypes, and epitopes which confer susceptibility or protection in the fibrosing autoimmune disease systemic sclerosis: Analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis. 2010;69(5):822–27.
PMID: 19596691. PMCID: PMC2916702. https://doi.org/10.1136/ard.2009.111906. Erratum in: Ann Rheum Dis. 2011;70(5):880.
11. Furukawa H, Oka S, Kawasaki A, Shimada K, Sugii S, Matsushita T, et al. Human leukocyte antigen and systemic sclerosis in Japanese: The sign of the four independent protective alleles, DRB1*13:02, DRB1*14:06, DQB1*03:01, and DPB1*02:01. PLoS ONE. 2016;11(4):e0154255.
PMID: 27116456. PMCID: PMC4846066. https://doi.org/10.1371/journal.pone.0154255
12. Hanson AL, Sahhar J, Ngian GS, Roddy J, Walker J, Stevens W, et al. Contribution of HLA and KIR alleles to systemic sclerosis susceptibility and immunological and clinical disease subtypes. Front Genet. 2022;13:913196.
PMID: 35754823. PMCID: PMC9214260. https://doi.org/10.3389/fgene.2022.913196
13. Stock CJW, De Lauretis A, Visca D, Daccord C, Kokosi M, Kouranos V, et al. Defining genetic risk factors for scleroderma-associated interstitial lung disease: IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease. Clin Rheumatol. 2020;39(4):1173–79.
PMID: 31916109. PMCID: PMC7142048. https://doi.org/10.1007/s10067-019-04922-6
14. Gonzalez-Serna D, Ochoa E, Lopez-Isac E, Julia A, Degenhardt F, Ortego-Centeno N, et al.; Scleroderma Genetic Consortium. A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease. Sci Rep. 2020;10(1):1862.
PMID: 32024964. PMCID: PMC7002703. https://doi.org/10.1038/s41598-020-58741-w
15. Ototake Y, Yamaguchi Y, Asami M, Komitsu N, Akita A, Watanabe T, et al. Downregulated IRF8 in monocytes and macrophages of patients with systemic sclerosis may aggravate the fibrotic phenotype. J Investig Dermatol. 2021;141(8):1954–63.
PMID: 33705797. https://doi.org/10.1016/j.jid.2021.02.015
16. Dieude P, Guedj M, Wipff J, Ruiz B, Hachulla E, Diot E, et al. STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis. Arthritis Rheum. 2009;60(8):2472–79.
PMID: 19644887. https://doi.org/10.1002/art.24688
17. Tsuchiya N, Kawasaki A, Hasegawa M, Fujimoto M, Takehara K, Kawaguchi Y, et al. Association of STAT4 polymorphism with systemic sclerosis in a Japanese population. Ann Rheum Dis. 2009;68(8):1375–76.
PMID: 19605749. https://doi.org/10.1136/ard.2009.111310
18. Lopez-Isac E, Campillo-Davo D, Bossini-Castillo L, Guerra SG, Assassi S, Simeon CP, et al. Influence of TYK2 in systemic sclerosis susceptibility: A new locus in the IL-12 pathway. Ann Rheum Dis. 2016;75(8):1521–26.
PMID: 26338038. PMCID: PMC7228811. https://doi.org/10.1136/annrheumdis-2015-208154
19. Broen JC, Bossini-Castillo L, van Bon L, Vonk MC, Knaapen H, Beretta L, et al.; Spanish Systemic Sclerosis Group. A rare polymorphism in the gene for Toll-like receptor 2 is associated with systemic sclerosis phenotype and increases the production of inflammatory mediators. Arthritis Rheum. 2012;64(1):264–71.
PMID: 21905008. https://doi.org/10.1002/art.33325
20. Liu C, Yan S, Chen H, Wu Z, Li L, Cheng L, et al. Association of GTF2I, NFKB1, and TYK2 regional polymorphisms with systemic sclerosis in a Chinese Han population. Front Immunol. 2021;12:640083.
PMID: 34248934. PMCID: PMC8261294. https://doi.org/10.3389/fimmu.2021.640083
21. Dieude P, Guedj M, Wipff J, Ruiz B, Riemekasten G, Matucci-Cerinic M, et al. Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population. Ann Rheum Dis. 2010;69(11):1958–64.
PMID: 20511617. https://doi.org/10.1136/ard.2009.127928
22. Bossini-Castillo L, Campillo-Davo D, Lopez-Isac E, Carmona FD, Simeon CP, Carreira P, et al. An MIF promoter polymorphism is associated with susceptibility to pulmonary arterial hypertension in diffuse cutaneous systemic sclerosis. J Rheumatol. 2017;44(10):1453–57.
PMID: 28668810. https://doi.org/10.3899/jrheum.161369
23. Dieude P, Bouaziz M, Guedj M, Riemekasten G, Airo P, Müller M, et al. Evidence of the contribution of the X chromosome to systemic sclerosis susceptibility: Association with the functional IRAK1 196Phe/532Ser haplotype. Arthritis Rheum. 2011;63(12):3979–87.
PMID: 21898345. https://doi.org/10.1002/art.30640
24. Lopez-Isac E, Bossini-Castillo L, Guerra SG, Denton C, Fonseca C, Assassi S, et al. Identification of IL12RB1 as a novel systemic sclerosis susceptibility locus. Arthritis Rheumatol. 2014;66(12):3521–23.
PMID: 25199642. PMCID: PMC4245383. https://doi.org/10.1002/art.38870
25. Bossini-Castillo L, Martin JE, Broen J, Gorlova O, Simeón CP, Beretta L, et al. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet. 2012;21(4):926–33.
PMID: 22076442. PMCID: PMC3298110. https://doi.org/10.1093/hmg/ddr522
26. Gourh P, Arnett FC, Tan FK, Assassi S, Divecha D, Paz G, et al. Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis. Ann Rheum Dis. 2010;69(3):550–55.
PMID: 19778912. PMCID: PMC2927683. https://doi.org/10.1136/ard.2009.116434
27. Beretta L, Cappiello F, Moore JH, Barili M, Greene CS, Scorza R. Ability of epistatic interactions of cytokine single-nucleotide polymorphisms to predict susceptibility to disease subsets in systemic sclerosis patients. Arthritis Rheum. 2008;59(7):974–83.
PMID: 18576303. https://doi.org/10.1002/art.23836
28. Trofimova AS, Mazurov VI, Trofimov EA. [Possibilities of hematopoietic stem cell transplantation in the treatment of systemic scleroderma. Terapiya = Therapy (Moscow). 2026;12(1):97–107 (In Russ.)].
EDN: FENUGV. https://doi.org/10.18565/therapy.2026.1.97-107
29. Zaripova L, Baigenzhin A, Zarkumova Z, Zhabakova Z, Boltanova A, Solomadin M, Pak A. Systemic sclerosis with interstitial lung disease: Identification of novel immunogenetic markers and ethnic specificity in Kazakh patients. Epidemiologia (Basel). 2025;6(3):41.
PMID: 40843700. PMCID: PMC12372110. https://doi.org/10.3390/epidemiologia6030041
30. Yang C, Tang S, Zhu D, Ding Y, Qiao J. Classical disease-specific autoantibodies in systemic sclerosis: Clinical features, gene susceptibility, and disease stratification. Front Med (Lausanne). 2020:7:587773.
PMID: 33330547. PMCID: PMC7710911. https://doi.org/10.3389/fmed.2020.587773
31. Gur C, Wang SY, Sheban F, Zada M, Li B, Kharouf F, et al. LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma. Cell. 2022;185(8):1373–88.e20.
PMID: 35381199. PMCID: PMC7612792. https://doi.org/10.1016/j.cell.2022.03.011
32. Manetti M, Allanore Y, Revillod L, Fatini C, Guiducci S, Cuomo G, et al. A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis. Arthritis Rheum. 2011;63(1):247–56.
PMID: 20967855. https://doi.org/10.1002/art.30101
33. Gladman DD, Kung TN, Siannis F, Pellett F, Farewell VT, Lee P. HLA markers for susceptibility and expression in scleroderma. J Rheumatol. 2005;32(8):1481–87. PMID: 16078323.
34. Wastowski IJ, Sampaio-Barros PD, Amstalden EM, Palomino GM, Marques-Neto JF, Crispim J, et al. HLA-G expression in the skin of patients with systemic sclerosis. J Rheumatol. 2009;36(6):1230–34.
PMID: 19369464. https://doi.org/10.3899/jrheum.080552
35. Khanna D, Hays RD, Maranian P, Seibold JR, Impens A, Mayes MD, et al. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. Arthritis Rheum. 2009;61(9):1257–63.
PMID: 19714600. PMCID: PMC2767193. https://doi.org/10.1002/art.24730
36. Rezaei R, Aslani S, Dashti N, Jamshidi A, Gharibdoost F, Mahmoudi M. Genetic implications in the pathogenesis of systemic sclerosis. Int J Rheum Dis. 2018;21(8):1478–86.
PMID: 30146749. https://doi.org/10.1111/1756-185X.13344
37. Demela P, Pirastu N, Soskic B. Cross-disorder genetic analysis of immune diseases reveals distinct gene associations that converge on common pathways. Nat Commun. 2023;14(1):2743.
PMID: 37173304. https://doi.org/10.1038/s41467-023-38389-6
38. Gourh P, Tan FK, Assassi S, Ahn CW, McNearney TA, Fischbach M, et al. Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis. Arthritis Rheum. 2006;54(12):3945–53.
PMID: 17133608. https://doi.org/10.1002/art.22196
39. Allanore Y. Pathophysiology of systemic sclerosis. Med Sci (Paris). 2016;32(2):183–91.
PMID: 26936176. https://doi.org/10.1051/medsci/20163202012
40. Elhai M, Meune C, Avouac J, Kahan A, Allanore Y. Trends in mortality in patients with systemic sclerosis over 40 years: A systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2012;51(6):1017–26.
78. PMID: 21900368. https://doi.org/10.1093/rheumatology/ker269
41. Martin JE, Assassi S, Diaz-Gallo LM, Broen JC, Simeon CP, Castellvi I, et al. A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. Hum Mol Genet. 2013;22(19):4021–29.
PMID: 23740937. PMCID: PMC3766185. https://doi.org/10.1093/hmg/ddt248
42. Stock CJW, Renzoni EA. Genetic predictors of systemic sclerosis-associated interstitial lung disease: A review of recent literature. Eur J Hum Genet. 2018;26(6):765–77.
PMID: 29476163. PMCID: PMC5974020. https://doi.org/10.1038/s41431-018-0104-8
43. Kumar M, Yip L, Wang F, Marty SE, Fathman CG. Autoimmune disease: Genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies? Front Immunol. 2025;16:1626082.
PMID: 40852720. PMCID: PMC12367657. https://doi.org/10.3389/fimmu.2025.1626082
44. Fatemah S Basingab. Exploring the role of genetic variants in susceptibility to autoimmune diseases: A molecular genetics approach. Hum Immunol. 2025;86(6):111614.
PMID: 41237580. https://doi.org/10.1016/j.humimm.2025.111614
45. Nasonov EL, Lila AM. [Inhibition of interleukin 6 in immune inflammatory rheumatic diseases: Achievements, prospects, and hopes. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2017;55(6):590–99 (In Russ.)].
EDN: YPXRAO. https://doi.org/10.14412/1995-4484-2017-590-599
Об авторах / Для корреспонденции
Anna S. Trofimova, MD, PhD (Medicine), associate professor of the Department of therapy and rheumatology named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University, Saint Petersburg, Russian Federation.E-mail: anna.trofimova@szgmu.ru
ORCID: https://orcid.org/0000-0001-5926-7912. eLibrary SPIN: 3083-7996
Marina A. Chernyavskaya, 6th-year student of the Institute of fundamental medicine, I.I. Mechnikov North-Western State Medical University, Saint Petersburg, Russian Federation.
E-mail: marina.chernyavskaya1904@gmail.com
ORCID: https://orcid.org/0009-0008-8527-9616. eLibrary SPIN: 2568-3847
Vadim I. Mazurov, MD, Dr. Sci. (Medicine), professor, Honored Scientist of the Russian Federation, academician of RAS, vice president of RSMSIM; chief scientific advisor, director of the Research institute of rheumatology, professor of the Department of therapy and rheumatology named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University; head of the Center for autoimmune diseases, V.A. Nasonova Clinical Rheumatological Hospital No. 25 (Saint Petersburg); chief external expert – rheumatologist of the Health Committee of the Government of Saint Petersburg, Saint Petersburg, Russian Federation.
E-mail: maz.nwgmu@yandex.ru
ORCID: https://orcid.org/0000-0002-0797-2051. Scopus ID: 16936315400. eLibrary SPIN: 6823-5482
Yana A. Leineman, MD, PhD (Medicine), associate professor of the Department of therapy and rheumatology named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University, Saint Petersburg, Russian Federation.
E-mail: leika15@yandex.ru
ORCID: https://orcid.org/0000-0003-2538-8112. eLibrary SPIN: 4832-4133
Evgeny A. Trofimov, MD, Dr. Sci. (Medicine), associate professor, head of the Department of therapy and rheumatology named after E.E. Eichwald, I.I. Mechnikov North-Western State Medical University, Saint Petersburg, Russian Federation.
E-mail: Evgeniy.trofimov@szgmu.ru
ORCID: https://orcid.org/0000-0003-3236-4485. Scopus ID: 57082588900. eLibrary SPIN: 4358-1663
Также по теме
