Advertisement

Seminars in Immunopathology

, Volume 37, Issue 5, pp 443–451 | Cite as

Genetics of systemic sclerosis

  • Lara Bossini-Castillo
  • Elena López-Isac
  • Maureen D. Mayes
  • Javier MartínEmail author
Review

Abstract

Systemic sclerosis (SSc) is connective tissue disorder in which fibrosis of the skin and internal organs is the main hallmark. Despite the difficulties of studying a complex disease, significant advances have been achieved in the SSc genetics field. In this review, we will describe the firmest genetic susceptibility markers known to date. We will analyze the most recent findings in the HLA region and in non-HLA genes. Furthermore, we will propose functional connections of these loci with the mechanisms involved in SSc pathogenesis. However, only non-HLA genetic regions that have been associated with SSc at the genome-wide significance level or that have been reported to be associated with the disease in at least two different independent studies will be considered. In spite of the increasing number of SSc genetic susceptibility factors identified, further studies with larger sample sizes, deeper phenotype characterization of the patients and innovative analyses will be needed to translate SSc genetics into clinical practice and patient care in the future.

Keywords

Systemic sclerosis Scleroderma Genetics Polymorphism SNP HLA 

Notes

Acknowledgments

This review was supported by the following grants: molecular reclassification to find clinically useful biomarkers for systemic autoimmune diseases (PRECISESAD) Innovative Medicines Initiative (IMI) partnership between the European Commission (FP7/2007-2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) (ref: 115565); Identificación de nuevos factores genéticos comunes en enfermedades autoinmunes sistémicas mediante el análisis conjunto de estudios de asociación del genoma completo (meta-GWAS). (BIO-1395) Proyecto de Excelencia, Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía; Beyond genome-wide association studies: new strategies for identifying genetic determinants of scleroderma (SAF2012-34435) Ministerio de Economía y Competitividad. Principal investigator was as follows: Prof. Javier Martín Ibáñez, MD, PhD.

References

  1. 1.
    Feghali-Bostwick C, Medsger TA Jr, Wright TM (2003) Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 48:1956–1963CrossRefPubMedGoogle Scholar
  2. 2.
    Arnett FC, Cho M, Chatterjee S, Aguilar MB, Reveille JD, Mayes MD (2001) Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum 44:1359–1362CrossRefPubMedGoogle Scholar
  3. 3.
    Hemminki K, Li X, Sundquist J, Sundquist K (2009) Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions. Arthritis Rheum 60:661–668CrossRefPubMedGoogle Scholar
  4. 4.
    Reveille JD, Fischbach M, McNearney T, Friedman AW, Aguilar MB, Lisse J et al (2001) Systemic sclerosis in 3 US ethnic groups: a comparison of clinical, sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum 30:332–346CrossRefPubMedGoogle Scholar
  5. 5.
    Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H et al (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42:D1001–1006PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661-678Google Scholar
  7. 7.
    Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R et al (2010) Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 42:426–429PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Gourh P et al (2006) Association of the PTPN22 R620 W polymorphism with anti-topoisomerase I- and anticentromere antibodypositive systemic sclerosis. Arthritis Rheum 54:3945–3953 Google Scholar
  9. 9.
    Dieude P et al (2008) The PTPN22 620 W allele confers susceptibility to sysremic sclerosis: Wndings of a large case-control study of european Causcasians and a meta-analysis. Arthritis Rheum 58:2183–2188Google Scholar
  10. 10.
    Zhou X, Lee JE, Arnett FC, Xiong M, Park MY, Yoo YK et al (2009) HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. Arthritis Rheum 60:3807–3814PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Allanore Y, Saad M, Dieude P, Avouac J, Distler JH, Amouyel P et al (2011) Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet 7:e1002091PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM et al (2008) Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet 4:e1000024PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Gilchrist FC, Bunn C, Foley PJ, Lympany PA, Black CM, Welsh KI et al (2001) Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP. Genes Immun 2:76–81CrossRefPubMedGoogle Scholar
  14. 14.
    Arnett FC, Gourh P, Shete S, Ahn CW, Honey RE, Agarwal SK et al (2010) 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 69:822–827PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Beretta L, Rueda B, Marchini M, Santaniello A, Simeon CP, Fonollosa V et al (2012) Analysis of Class II human leucocyte antigens in Italian and Spanish systemic sclerosis. Rheumatology (Oxford) 51:52–59CrossRefGoogle Scholar
  16. 16.
    Parkes M, Cortes A, van Heel DA, Brown MA (2013) Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 14:661–673CrossRefPubMedGoogle Scholar
  17. 17.
    Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X et al (2012) Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 44:291–296PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Mayes MD, Bossini-Castillo L, Gorlova O, Martin JE, Zhou X, Chen WV et al (2014) Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis. Am J Hum Genet 94:47–61PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Rapin N, Hoof I, Lund O, Nielsen M (2008) MHC motif viewer. Immunogenetics 60:759–765PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Nielsen M, Lundegaard C, Blicher T, Peters B, Sette A, Justesen S et al (2008) Quantitative predictions of peptide binding to any HLA-DR molecule of known sequence: NetMHCIIpan. PLoS Comput Biol 4:e1000107PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Albert FW, Kruglyak L (2015) The role of regulatory variation in complex traits and disease. Nat Rev Genet 16:197–212CrossRefPubMedGoogle Scholar
  22. 22.
    Crouse J, Kalinke U, Oxenius A (2015) Regulation of antiviral T cell responses by type I interferons. Nat Rev Immunol 15:231–242CrossRefPubMedGoogle Scholar
  23. 23.
    van Bon L, Affandi AJ, Broen J, Christmann RB, Marijnissen RJ, Stawski L et al (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 370:433–443PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Wu M, Assassi S (2013) The role of type 1 interferon in systemic sclerosis. Front Immunol 4:266PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Barnes BJ, Richards J, Mancl M, Hanash S, Beretta L, Pitha PM (2004) Global and distinct targets of IRF-5 and IRF-7 during innate response to viral infection. J Biol Chem 279:45194–45207CrossRefPubMedGoogle Scholar
  26. 26.
    Ryzhakov G, Eames HL, Udalova IA (2015) Activation and function of interferon regulatory factor 5. J Interf Cytokine Res: Off J Int Soc Interf Cytokine Res 35:71–78CrossRefGoogle Scholar
  27. 27.
    Ito I, Kawaguchi Y, Kawasaki A, Hasegawa M, Ohashi J, Hikami K et al (2009) Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese population. Arthritis Rheum 60:1845–1850CrossRefPubMedGoogle Scholar
  28. 28.
    Dieude P, Guedj M, Wipff J, Avouac J, Fajardy I, Diot E et al (2009) Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis. Arthritis Rheum 60:225–233CrossRefPubMedGoogle Scholar
  29. 29.
    Dieude P, Dawidowicz K, Guedj M, Legrain Y, Wipff J, Hachulla E et al (2010) Phenotype-haplotype correlation of IRF5 in systemic sclerosis: role of 2 haplotypes in disease severity. J Rheumatol 37:987–992CrossRefPubMedGoogle Scholar
  30. 30.
    Carmona FD, Martin JE, Beretta L, Simeon CP, Carreira PE, Callejas JL et al (2013) The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis. PLoS One 8:e54419PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Kottyan LC, Zoller EE, Bene J, Lu X, Kelly JA, Rupert AM et al (2015) The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet 24:582–596CrossRefPubMedGoogle Scholar
  32. 32.
    Sharif R, Mayes MD, Tan FK, Gorlova OY, Hummers LK, Shah AA et al (2012) IRF5 polymorphism predicts prognosis in patients with systemic sclerosis. Ann Rheum Dis 71:1197–1202PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Gorlova O, Martin JE, Rueda B, Koeleman BP, Ying J, Teruel M et al (2011) Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet 7:e1002178PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Wang H, Morse HC 3rd (2009) IRF8 regulates myeloid and B lymphoid lineage diversification. Immunol Res 43:109–117PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Carmona FD, Gutala R, Simeon CP, Carreira P, Ortego-Centeno N, Vicente-Rabaneda E et al (2012) Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis. Ann Rheum Dis 71:114–119PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T et al (2005) IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434:772–777CrossRefPubMedGoogle Scholar
  37. 37.
    Trinchieri G (1997) Function and clinical use of interleukin-12. Curr Opin Hematol 4:59–66CrossRefPubMedGoogle Scholar
  38. 38.
    van Wanrooij RL, Zwiers A, Kraal G, Bouma G (2012) Genetic variations in interleukin-12 related genes in immune-mediated diseases. J Autoimmun 39:359–368CrossRefPubMedGoogle Scholar
  39. 39.
    Bossini-Castillo L, Martin JE, Broen J, Gorlova O, Simeon CP, Beretta L et al (2012) A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet 21:926–933PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Lopez-Isac E, Bossini-Castillo L, Guerra SG, Denton C, Fonseca C, Assassi S et al (2014) Identification of IL12RB1 as a novel systemic sclerosis susceptibility locus. Arthritis Rheum 66:3521–3523CrossRefGoogle Scholar
  41. 41.
    Liang Y, Pan HF, Ye DQ (2014) Therapeutic potential of STAT4 in autoimmunity. Expert Opin Ther Targets 18:945–960CrossRefPubMedGoogle Scholar
  42. 42.
    Nguyen KB, Watford WT, Salomon R, Hofmann SR, Pien GC, Morinobu A et al (2002) Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science 297:2063–2066CrossRefPubMedGoogle Scholar
  43. 43.
    Rueda B, Broen J, Simeon C, Hesselstrand R, Diaz B, Suarez H et al (2009) The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet 18:2071–2077CrossRefPubMedGoogle Scholar
  44. 44.
    Dieude P, Guedj M, Wipff J, Ruiz B, Hachulla E, Diot E et al (2009) STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis. Arthritis Rheum 60:2472–2479CrossRefPubMedGoogle Scholar
  45. 45.
    Gourh P, Agarwal SK, Divecha D, Assassi S, Paz G, Arora-Singh RK et al (2009) Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines. Arthritis Rheum 60:3794–3806PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Tsuchiya N, Kawasaki A, Hasegawa M, Fujimoto M, Takehara K, Kawaguchi Y et al (2009) Association of STAT4 polymorphism with systemic sclerosis in a Japanese population. Ann Rheum Dis 68:1375–1376CrossRefPubMedGoogle Scholar
  47. 47.
    Yi L, Wang JC, Guo XJ, Gu YH, Tu WZ, Guo G et al (2013) STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population. Int J Immunopathol Pharmacol 26:473–478PubMedCentralPubMedGoogle Scholar
  48. 48.
    Avouac J, Furnrohr BG, Tomcik M, Palumbo K, Zerr P, Horn A et al (2011) Inactivation of the transcription factor STAT-4 prevents inflammation-driven fibrosis in animal models of systemic sclerosis. Arthritis Rheum 63:800–809CrossRefPubMedGoogle Scholar
  49. 49.
    Barnes J, Agarwal SK (2011) Targeting STAT4 in systemic sclerosis: a promising new direction. Expert Rev Clin Immunol 7:445–448PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Rodriguez AM, Rodin D, Nomura H, Morton CC, Weremowicz S, Schneider MC (1997) Identification, localization, and expression of two novel human genes similar to deoxyribonuclease I. Genomics 42:507–513CrossRefPubMedGoogle Scholar
  51. 51.
    Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F, Alhashmi N et al (2011) Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet 43:1186–1188CrossRefPubMedGoogle Scholar
  52. 52.
    Ueki M, Kimura-Kataoka K, Takeshita H, Fujihara J, Iida R, Sano R et al (2014) Evaluation of all non-synonymous single nucleotide polymorphisms (SNPs) in the genes encoding human deoxyribonuclease I and I-like 3 as a functional SNP potentially implicated in autoimmunity. FEBS J 281:376–390CrossRefPubMedGoogle Scholar
  53. 53.
    Zochling J, Newell F, Charlesworth JC, Leo P, Stankovich J, Cortes A et al (2014) An Immunochip-based interrogation of scleroderma susceptibility variants identifies a novel association at DNASE1L3. Arthritis Res Ther 16:438PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Martin JE, Assassi S, Diaz-Gallo LM, Broen JC, Simeon CP, Castellvi I et al (2013) A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. Hum Mol Genet 22:4021–4029PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Bhattacharya A, Eissa NT (2013) Autophagy and autoimmunity crosstalks. Front Immunol 4:88PubMedCentralCrossRefPubMedGoogle Scholar
  56. 56.
    Lopez-Isac E, Bossini-Castillo L, Simeon CP, Egurbide MV, Alegre-Sancho JJ, Callejas JL et al (2014) A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility. Arthritis Res Ther 16:R6PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Wei J, Zhu H, Komura K, Lord G, Tomcik M, Wang W et al (2014) A synthetic PPAR-gamma agonist triterpenoid ameliorates experimental fibrosis: PPAR-gamma-independent suppression of fibrotic responses. Ann Rheum Dis 73:446–454PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    O'Reilly S, Hugle T, van Laar JM (2012) T cells in systemic sclerosis: a reappraisal. Rheumatology (Oxford) 51:1540–1549CrossRefGoogle Scholar
  59. 59.
    Dieude P, Boileau C, Guedj M, Avouac J, Ruiz B, Hachulla E et al (2011) Independent replication establishes the CD247 gene as a genetic systemic sclerosis susceptibility factor. Ann Rheum Dis 70:1695–1696CrossRefPubMedGoogle Scholar
  60. 60.
    Wang J, Yi L, Guo X, He D, Li H, Guo G et al (2014) Lack of Association of the CD247 SNP rs2056626 with systemic sclerosis in Han Chinese. Open Rheum J 8:43–45CrossRefGoogle Scholar
  61. 61.
    Okada M (2012) Regulation of the SRC family kinases by Csk. Int J Biol Sci 8:1385–1397PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Martin JE, Broen JC, Carmona FD, Teruel M, Simeon CP, Vonk MC et al (2012) Identification of CSK as a systemic sclerosis genetic risk factor through genome wide association study follow-up. Hum Mol Genet 21:2825–2835PubMedCentralCrossRefPubMedGoogle Scholar
  63. 63.
    Vang T, Liu WH, Delacroix L, Wu S, Vasile S, Dahl R et al (2012) LYP inhibits T-cell activation when dissociated from CSK. Nat Chem Biol 8:437–446PubMedCentralCrossRefPubMedGoogle Scholar
  64. 64.
    Fiorillo E, Orru V, Stanford SM, Liu Y, Salek M, Rapini N et al (2010) Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. J Biol Chem 285:26506–26518PubMedCentralCrossRefPubMedGoogle Scholar
  65. 65.
    Diaz-Gallo LM, Gourh P, Broen J, Simeon C, Fonollosa V, Ortego-Centeno N et al (2011) Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis. Ann Rheum Dis 70:454–462PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    Yoshizaki A, Sato S (2015) Abnormal B lymphocyte activation and function in systemic sclerosis. Ann Dermatol 27:1–9PubMedCentralCrossRefPubMedGoogle Scholar
  67. 67.
    Dieude P, Wipff J, Guedj M, Ruiz B, Melchers I, Hachulla E et al (2009) BANK1 is a genetic risk factor for diffuse cutaneous systemic sclerosis and has additive effects with IRF5 and STAT4. Arthritis Rheum 60:3447–3454CrossRefPubMedGoogle Scholar
  68. 68.
    Rueda B, Gourh P, Broen J, Agarwal SK, Simeon C, Ortego-Centeno N et al (2010) BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians. Ann Rheum Dis 69:700–705PubMedCentralCrossRefPubMedGoogle Scholar
  69. 69.
    Coustet B, Dieude P, Guedj M, Bouaziz M, Avouac J, Ruiz B et al (2011) C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: results from a large french cohort and meta-analysis. Arthritis Rheum 63:2091–2096CrossRefPubMedGoogle Scholar
  70. 70.
    Ito I, Kawaguchi Y, Kawasaki A, Hasegawa M, Ohashi J, Kawamoto M et al (2010) Association of the FAM167A-BLK region with systemic sclerosis. Arthritis Rheum 62:890–895CrossRefPubMedGoogle Scholar
  71. 71.
    Gourh P, Agarwal SK, Martin E, Divecha D, Rueda B, Bunting H et al (2010) Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations. J Autoimmun 34:155–162PubMedCentralCrossRefPubMedGoogle Scholar
  72. 72.
    Shu C, Du W, Mao X, Li Y, Zhu Q, Wang W et al (2014) Possible single-nucleotide polymorphism loci associated with systemic sclerosis susceptibility: a genetic association study in a Chinese Han population. PLoS One 9:e113197PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Hugle T, O'Reilly S, Simpson R, Kraaij MD, Bigley V, Collin M et al (2013) Tumor necrosis factor-costimulated T lymphocytes from patients with systemic sclerosis trigger collagen production in fibroblasts. Arthritis Rheum 65:481–491CrossRefPubMedGoogle Scholar
  74. 74.
    Murdaca G, Spano F, Contatore M, Guastalla A, Puppo F (2014) Potential use of TNF-alpha inhibitors in systemic sclerosis. Immunotherapy 6:283–289CrossRefPubMedGoogle Scholar
  75. 75.
    Catrysse L, Vereecke L, Beyaert R, van Loo G (2014) A20 in inflammation and autoimmunity. Trends Immunol 35:22–31CrossRefPubMedGoogle Scholar
  76. 76.
    Dieude P, Guedj M, Wipff J, Ruiz B, Riemekasten G, Matucci-Cerinic M et al (2010) Association of the TNFAIP3 rs5029939 variant with systemic sclerosis in the European Caucasian population. Ann Rheum Dis 69:1958–1964CrossRefPubMedGoogle Scholar
  77. 77.
    Koumakis E, Giraud M, Dieude P, Cohignac V, Cuomo G, Airo P et al (2012) 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 64:2746–2752CrossRefPubMedGoogle Scholar
  78. 78.
    Bossini-Castillo L, Martin JE, Broen J, Simeon CP, Beretta L, Gorlova OY et al (2013) Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study. Ann Rheum Dis 72:602–607CrossRefPubMedGoogle Scholar
  79. 79.
    Gough MJ, Weinberg AD (2009) OX40 (CD134) and OX40L. Adv Exp Med Biol 647:94–107CrossRefPubMedGoogle Scholar
  80. 80.
    Ishii N, Takahashi T, Soroosh P, Sugamura K (2010) OX40-OX40 ligand interaction in T-cell-mediated immunity and immunopathology. Adv Immunol 105:63–98CrossRefPubMedGoogle Scholar
  81. 81.
    Gourh P, Arnett FC, Tan FK, Assassi S, Divecha D, Paz G et al (2010) Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis. Ann Rheum Dis 69:550–555PubMedCentralCrossRefPubMedGoogle Scholar
  82. 82.
    Bossini-Castillo L, Broen JC, Simeon CP, Beretta L, Vonk MC, Ortego-Centeno N et al (2011) A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort. Ann Rheum Dis 70:638–641CrossRefPubMedGoogle Scholar
  83. 83.
    Coustet B, Bouaziz M, Dieude P, Guedj M, Bossini-Castillo L, Agarwal S et al (2012) 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 Rheum 39:997–1003PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Lara Bossini-Castillo
    • 1
  • Elena López-Isac
    • 1
  • Maureen D. Mayes
    • 2
  • Javier Martín
    • 1
    Email author
  1. 1.Consejo Superior de Investigaciones Científicas (IPBLN-CSIC)Instituto de Parasitología y Biomedicina López-Neyra, PTS GrandaGranadaSpain
  2. 2.The University of Texas Health Science Center at HoustonHoustonUSA

Personalised recommendations