Skip to main content
SpringerLink
Log in

Genetics of Systemic Sclerosis

  • Chapter
  • First Online:
Systemic Sclerosis

Abstract

Genetic epidemiology suggests that the molecular background of systemic sclerosis (SSc) such as autoantibody production or gene expression profiles may be highly hereditary; however, the clinical occurrence of SSc may require non-hereditary factor(s). Genome-wide association studies (GWASs) confirmed that the HLA genes are the strongest genetic factors, although specific risk alleles are different among populations and among the clinical subsets such as those determined by autoantibody profiles. GWAS and candidate gene studies revealed more than a dozen of convincing candidate genes; however, thus far, all of them are shared by other diseases and do not appear to explain the unique features of SSc such as extensive fibrosis and vascular damage. Thus, something must be missing, and more studies are required to reveal the secrets of this enigmatic disease. Here, we reviewed the genetic studies of SSc, with emphasis on those performed on Asian populations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Arnett FC, Cho M, Chatterjee S, Aguilar MB, Reveille JD, Mayes MD. Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 2001;44(6):1359–62.

    Article  CAS  PubMed  Google Scholar 

  2. Feghali-Bostwick C, Medsger Jr TA, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum. 2003;48(7):1956–63. doi:10.1002/art.11173.

    Article  PubMed  Google Scholar 

  3. Zhou X, Tan FK, Xiong M, Arnett FC, Feghali-Bostwick CA. Monozygotic twins clinically discordant for scleroderma show concordance for fibroblast gene expression profiles. Arthritis Rheum. 2005;52(10):3305–14. doi:10.1002/art.21355.

    Article  CAS  PubMed  Google Scholar 

  4. Tager RE, Tikly M. Clinical and laboratory manifestations of systemic sclerosis (scleroderma) in Black South Africans. Rheumatology. 1999;38(5):397–400.

    Article  CAS  PubMed  Google Scholar 

  5. Mayes MD, Lacey Jr JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48(8):2246–55. doi:10.1002/art.11073.

    Article  PubMed  Google Scholar 

  6. McNeilage LJ, Youngchaiyud U, Whittingham S. Racial differences in antinuclear antibody patterns and clinical manifestations of scleroderma. Arthritis Rheum. 1989;32(1):54–60.

    Article  CAS  PubMed  Google Scholar 

  7. Kuwana M, Inoko H, Kameda H, Nojima T, Sato S, Nakamura K, et al. Association of human leukocyte antigen class II genes with autoantibody profiles, but not with disease susceptibility in Japanese patients with systemic sclerosis. Intern Med. 1999;38(4):336–44.

    Article  CAS  PubMed  Google Scholar 

  8. Kuwana M, Kaburaki J, Arnett FC, Howard RF, Medsger Jr TA, Wright TM. Influence of ethnic background on clinical and serologic features in patients with systemic sclerosis and anti-DNA topoisomerase I antibody. Arthritis Rheum. 1999;42(3):465–74.

    Article  CAS  PubMed  Google Scholar 

  9. Kuwana M, Kaburaki J, Okano Y, Inoko H, Tsuji K. The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma). J Clin Invest. 1993;92(3):1296–301. doi:10.1172/JCI116703.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Odani T, Yasuda S, Ota Y, Fujieda Y, Kon Y, Horita T, et al. Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA-DRB5*01:05 allele in scleroderma patients with interstitial lung disease. Rheumatology. 2012;51(10):1765–74. doi:10.1093/rheumatology/kes149.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou X, Lee JE, Arnett FC, Xiong M, Park MY, Yoo YK, et al. HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. Arthritis Rheum. 2009;60(12):3807–14. doi:10.1002/art.24982.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Kang SH, Park MH, Song EY, Kang SJ, Lee EB, Song YW, et al. Association of HLA class II genes with systemic sclerosis in Koreans. J Rheumatol. 2001;28(7):1577–83.

    CAS  PubMed  Google Scholar 

  13. Wang J, Guo X, Yi L, Guo G, Tu W, Wu W, et al. Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population. PLoS One. 2014;9(1):e87363. doi:10.1371/journal.pone.0087363.

    Article  PubMed Central  PubMed  Google Scholar 

  14. He D, Wang J, Yi L, Guo X, Guo S, Guo G, et al. Association of the HLA-DRB1 with scleroderma in Chinese population. PLoS One. 2014;9(9):e106939. doi:10.1371/journal.pone.0106939.

    Article  PubMed Central  PubMed  Google Scholar 

  15. 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 systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann Rheum Dis. 2010;69(5):822–7. doi:10.1136/ard.2009.111906.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Loubiere LS, Lambert NC, Madeleine MM, Porter AJ, Mullarkey ME, Pang JM, et al. HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women. Rheumatology. 2005;44(3):318–22. doi:10.1093/rheumatology/keh489.

    Article  CAS  PubMed  Google Scholar 

  17. Mayes MD, Bossini-Castillo L, Gorlova O, Martin JE, Zhou X, Chen WV, et al. Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am J Hum Genet. 2014;94(1):47–61. doi:10.1016/j.ajhg.2013.12.002.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Azzouz DF, Rak JM, Fajardy I, Allanore Y, Tiev KP, Farge-Bancel D, et al. Comparing HLA shared epitopes in French Caucasian patients with scleroderma. PLoS One. 2012;7(5):e36870. doi:10.1371/journal.pone.0036870.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Grigolo B, Mazzetti I, Meliconi R, Bazzi S, Scorza R, Candela M, et al. Anti-topoisomerase II alpha autoantibodies in systemic sclerosis-association with pulmonary hypertension and HLA-B35. Clin Exp Immunol. 2000;121(3):539–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Beretta L, Rueda B, Marchini M, Santaniello A, Simeon CP, Fonollosa V, et al. Analysis of Class II human leucocyte antigens in Italian and Spanish systemic sclerosis. Rheumatology. 2012;51(1):52–9. doi:10.1093/rheumatology/ker335.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Tikly M, Rands A, McHugh N, Wordsworth P, Welsh K. Human leukocyte antigen class II associations with systemic sclerosis in South Africans. Tissue Antigens. 2004;63(5):487–90. doi:10.1111/j.0001-2815.2004.00199.x.

    Article  CAS  PubMed  Google Scholar 

  22. Nguyen B, Mayes MD, Arnett FC, del Junco D, Reveille JD, Gonzalez EB, et al. HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis. Arthritis Rheum. 2011;63(2):530–4. doi:10.1002/art.30111.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Kuwana M, Okano Y, Kaburaki J, Inoko H. HLA class II genes associated with anticentromere antibody in Japanese patients with systemic sclerosis (scleroderma). Ann Rheum Dis. 1995;54(12):983–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Kuwana M, Okano Y, Kaburaki J, Tojo T, Medsger Jr TA. Racial differences in the distribution of systemic sclerosis-related serum antinuclear antibodies. Arthritis Rheum. 1994;37(6):902–6.

    Article  CAS  PubMed  Google Scholar 

  25. Kuwana M, Kaburaki J, Mimori T, Tojo T, Homma M. Autoantigenic epitopes on DNA topoisomerase I. Clinical and immunogenetic associations in systemic sclerosis. Arthritis Rheum. 1993;36(10):1406–13.

    Article  CAS  PubMed  Google Scholar 

  26. Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42(Database issue):D1001–6. doi:10.1093/nar/gkt1229.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R, et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet. 2010;42(5):426–9. doi:10.1038/ng.565.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Allanore Y, Saad M, Dieude P, Avouac J, Distler JH, Amouyel P, et al. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet. 2011;7(7):e1002091. doi:10.1371/journal.pgen.1002091.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Gorlova O, Martin JE, Rueda B, Koeleman BP, Ying J, Teruel M, et al. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet. 2011;7(7):e1002178. doi:10.1371/journal.pgen.1002178.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. 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):4021–9. doi:10.1093/hmg/ddt248.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Martin JE, Broen JC, Carmona FD, Teruel M, Simeon CP, Vonk MC, et al. Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up. Hum Mol Genet. 2012;21(12):2825–35. doi:10.1093/hmg/dds099.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. 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):3521–3. doi:10.1002/art.38870.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Bossini-Castillo L, Martin JE, Broen J, Gorlova O, Simeon 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. doi:10.1093/hmg/ddr522.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Ito I, Kawaguchi Y, Kawasaki A, Hasegawa M, Ohashi J, Hikami K, et al. Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese population. Arthritis Rheum. 2009;60(6):1845–50. doi:10.1002/art.24600.

    Article  CAS  PubMed  Google Scholar 

  35. Terao C, Ohmura K, Kawaguchi Y, Nishimoto T, Kawasaki A, Takehara K, et al. PLD4 as a novel susceptibility gene for systemic sclerosis in a Japanese population. Arthritis Rheum. 2013;65(2):472–80. doi:10.1002/art.37777.

    Article  CAS  PubMed  Google Scholar 

  36. 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):1375–6. doi:10.1136/ard.2009.111310.

    Article  CAS  PubMed  Google Scholar 

  37. Koumakis E, Giraud M, Dieude P, Cohignac V, Cuomo G, Airo P, et al. Brief report: candidate gene study in systemic sclerosis identifies a rare and functional variant of the TNFAIP3 locus as a risk factor for polyautoimmunity. Arthritis Rheum. 2012;64(8):2746–52. doi:10.1002/art.34490.

    Article  CAS  PubMed  Google Scholar 

  38. 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. doi:10.1136/ard.2009.127928.

    Article  CAS  PubMed  Google Scholar 

  39. Coustet B, Bouaziz M, Dieude P, Guedj M, Bossini-Castillo L, Agarwal S, et al. Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis. J Rheumatol. 2012;39(5):997–1003. doi:10.3899/jrheum.111270.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. 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. doi:10.1136/ard.2010.141838.

    Article  CAS  PubMed  Google Scholar 

  41. Rueda B, Gourh P, Broen J, Agarwal SK, Simeon C, Ortego-Centeno N, et al. BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians. Ann Rheum Dis. 2010;69(4):700–5. doi:10.1136/ard.2009.118174.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Dieude P, Wipff J, Guedj M, Ruiz B, Melchers I, Hachulla E, et al. BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4. Arthritis Rheum. 2009;60(11):3447–54. doi:10.1002/art.24885.

    Article  CAS  PubMed  Google Scholar 

  43. Ito I, Kawaguchi Y, Kawasaki A, Hasegawa M, Ohashi J, Kawamoto M, et al. Association of the FAM167A-BLK region with systemic sclerosis. Arthritis Rheum. 2010;62(3):890–5. doi:10.1002/art.27303.

    Article  CAS  PubMed  Google Scholar 

  44. Gourh P, Agarwal SK, Martin E, Divecha D, Rueda B, Bunting H, et al. Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations. J Autoimmun. 2010;34(2):155–62. doi:10.1016/j.jaut.2009.08.014.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Hoshino K, Satoh T, Kawaguchi Y, Kuwana M. Association of hepatocyte growth factor promoter polymorphism with severity of interstitial lung disease in Japanese patients with systemic sclerosis. Arthritis Rheum. 2011;63(8):2465–72. doi:10.1002/art.30415.

    Article  CAS  PubMed  Google Scholar 

  46. Tsuchiya N, Kuroki K, Fujimoto M, Murakami Y, Tedder TF, Tokunaga K, et al. Association of a functional CD19 polymorphism with susceptibility to systemic sclerosis. Arthritis Rheum. 2004;50(12):4002–7. doi:10.1002/art.20674.

    Article  CAS  PubMed  Google Scholar 

  47. Hitomi Y, Tsuchiya N, Hasegawa M, Fujimoto M, Takehara K, Tokunaga K, et al. Association of CD22 gene polymorphism with susceptibility to limited cutaneous systemic sclerosis. Tissue Antigens. 2007;69(3):242–9. doi:10.1111/j.1399-0039.2007.00801.x.

    Article  CAS  PubMed  Google Scholar 

  48. Fujimoto M, Sato S. B cell signaling and autoimmune diseases: CD19/CD22 loop as a B cell signaling device to regulate the balance of autoimmunity. J Dermatol Sci. 2007;46(1):1–9. doi:10.1016/j.jdermsci.2006.12.004.

    Article  CAS  PubMed  Google Scholar 

  49. Hikami K, Ehara Y, Hasegawa M, Fujimoto M, Matsushita M, Oka T, et al. Association of IL-10 receptor 2 (IL10RB) SNP with systemic sclerosis. Biochem Biophys Res Commun. 2008;373(3):403–7. doi:10.1016/j.bbrc.2008.06.054.

    Article  CAS  PubMed  Google Scholar 

  50. Hasebe N, Kawasaki A, Ito I, Kawamoto M, Hasegawa M, Fujimoto M, et al. Association of UBE2L3 polymorphisms with diffuse cutaneous systemic sclerosis in a Japanese population. Ann Rheum Dis. 2012;71(7):1259–60. doi:10.1136/annrheumdis-2011-201091.

    Article  CAS  PubMed  Google Scholar 

  51. Korman BD, Criswell LA. Recent advances in the genetics of systemic sclerosis: toward biological and clinical significance. Curr Rheumatol Rep. 2015;17(3):21. doi:10.1007/s11926-014-0484-x.

    Article  PubMed Central  PubMed  Google Scholar 

  52. Broen JC, Radstake TR, Rossato M. The role of genetics and epigenetics in the pathogenesis of systemic sclerosis. Nat Rev Rheumatol. 2014;10(11):671–81. doi:10.1038/nrrheum.2014.128.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Naoyuki Tsuchiya & Aya Kawasaki

Authors
  1. Naoyuki Tsuchiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aya Kawasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Naoyuki Tsuchiya .

Editor information

Editors and Affiliations

  1. Department of Dermatology, Kanazawa University, Kanazawa, Ishikawa, Japan

    Kazuhiko Takehara

  2. Department of Dermatology, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Manabu Fujimoto

  3. Department of Allergy and Rheumatology, Nippon Medical School, Tokyo, Tokyo, Japan

    Masataka Kuwana

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Japan

About this chapter

Cite this chapter

Tsuchiya, N., Kawasaki, A. (2016). Genetics of Systemic Sclerosis. In: Takehara, K., Fujimoto, M., Kuwana, M. (eds) Systemic Sclerosis. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55708-1_5

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-55708-1_5

  • Published:

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-55707-4

  • Online ISBN: 978-4-431-55708-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation