Rheumatology International

, Volume 34, Issue 10, pp 1401–1408

Genetic polymorphisms of dsRNA ligating pattern recognition receptors TLR3, MDA5, and RIG-I. Association with systemic lupus erythematosus and clinical phenotypes

  • C. Enevold
  • L. Kjær
  • C. H. Nielsen
  • A. Voss
  • R. S. Jacobsen
  • M. L. F. Hermansen
  • L. Redder
  • A. B. Oturai
  • P. E. Jensen
  • K. Bendtzen
  • S. Jacobsen
Original Article

Abstract

This study aimed to demonstrate possible associations between genetic polymorphisms in Toll-like receptor 3, interferon induced with helicase C domain 1 (IFIH1) and DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 and systemic lupus erythematosus (SLE), including the phenotypes lupus nephritis and malar rash, as well as the presence of autoantibodies against nucleic acid-containing complexes. Genotyping was carried out in two Danish cohorts [Copenhagen (CPH) and Odense (ODE)] totaling 344 patients and was compared with 641 previously genotyped healthy controls. In the ODE cohort, the patients were only genotyped for the rs1990760 polymorphism of IFIH1. Single nucleotide polymorphisms (SNPs) were determined by a multiplex bead-based assay (CPH cohort) or real-time PCR (ODE cohort). Associations were investigated using the Cochran–Armitage trend test. The odds ratio (OR) for minor allele homozygotes versus major allele homozygotes suggested a protective effect of the IFIH1 rs1990760 SNP for SLE in the ODE cohort [OR 0.52, 95 % confidence intervals (95 % CI) 0.31–0.88, Pcorr. = 0.05] but not in the CPH cohort, although the OR suggested a trend in the same direction, and when combining the two patient cohorts, ORs were 0.57, 95 % CI 0.37–0.88. None of the other investigated polymorphisms showed any association with SLE. Regarding phenotypes, we found a statistically significant association between rs1990760 and malar rash in the CPH cohort, with ORs suggesting a protective effect (OR 0.28, 95 % CI 0.13–0.62 for heterozygotes and OR 0.11, 95 % CI 0.03–0.41 for homozygotes, Pcorr. = 0.0001). There were no significant associations between rs1990760 and presence of anti-dsDNA, anti-U1RNP, or anti-Smith antibodies. Our study supports previous findings of an association between the rs1990760 polymorphism of IFIH1 and SLE and indicates that this SNP may also be associated with malar rash in SLE patients although this finding needs confirmation.

Keywords

SLE IFIH1 MDA5 RIG-I DDX58 TLR3 rs1990760 

References

  1. 1.
    Jacobsen S, Petersen J, Ullman S, Junker P, Voss A, Rasmussen JM et al (1998) A multicentre study of 513 Danish patients with systemic lupus erythematosus. II. Disease mortality and clinical factors of prognostic value. Clin Rheumatol 17:478–484PubMedCrossRefGoogle Scholar
  2. 2.
    Jacobsen S, Petersen J, Ullman S, Junker P, Voss A, Rasmussen JM et al (1998) A multicentre study of 513 Danish patients with systemic lupus erythematosus. I. Disease manifestations and analyses of clinical subsets. Clin Rheumatol 17:468–477PubMedCrossRefGoogle Scholar
  3. 3.
    Nielsen CT, Østergaard O, Johnsen C, Jacobsen S, Heegaard NHH (2011) Distinct features of circulating microparticles and their relationship to clinical manifestations in systemic lupus erythematosus. Arthritis Rheum 63:3067–3077PubMedCrossRefGoogle Scholar
  4. 4.
    Celhar T, Magalhães R, Fairhurst A-M (2012) TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunol Res 53:58–77PubMedCrossRefGoogle Scholar
  5. 5.
    Rönnblom L, Alm GV, Eloranta M-L (2011) The type I interferon system in the development of lupus. Semin Immunol 23:113–121PubMedCrossRefGoogle Scholar
  6. 6.
    Honda K, Taniguchi T (2006) IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6:644–658PubMedCrossRefGoogle Scholar
  7. 7.
    Midgley A, Thorbinson C, Beresford MW (2012) Expression of Toll-like receptors and their detection of nuclear self-antigen leading to immune activation in JSLE. Rheumatology (Oxford) 51:824–832CrossRefGoogle Scholar
  8. 8.
    Martin DA, Elkon KB (2005) Autoantibodies make a U-turn: the toll hypothesis for autoantibody specificity. J Exp Med 202:1465–1469PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Komatsuda A, Wakui H, Iwamoto K, Ozawa M, Togashi M, Masai R et al (2008) Up-regulated expression of Toll-like receptors mRNAs in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Clin Exp Immunol 152:482–487PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Wu O, Chen GP, Chen H, Li XP, Xu JH, Zhao SS et al (2009) The expressions of Toll-like receptor 9 and T-bet in circulating B and T cells in newly diagnosed, untreated systemic lupus erythematosus and correlations with disease activity and laboratory data in a Chinese population. Immunobiology 214:392–402PubMedCrossRefGoogle Scholar
  11. 11.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738PubMedCrossRefGoogle Scholar
  12. 12.
    Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X et al (2009) A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41:1228–1233PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Gono T, Kawaguchi Y, Sugiura T, Furuya T, Kawamoto M, Hanaoka M et al (2010) Interferon-induced helicase (IFIH1) polymorphism with systemic lupus erythematosus and dermatomyositis/polymyositis. Mod Rheumatol 20:466–470PubMedCrossRefGoogle Scholar
  14. 14.
    Cen H, Wang W, Leng R-X, Wang T-Y, Pan H-F, Fan Y-G et al (2013) Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: a meta-analysis. Autoimmunity 6934:1–8Google Scholar
  15. 15.
    Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, Garnier S et al (2008) Association of systemic lupus erythematosus with C8orf13–BLK and ITGAM–ITGAX. N Engl J Med 358:900–909PubMedCrossRefGoogle Scholar
  16. 16.
    Imaizumi T, Arikawa T, Sato T, Uesato R, Matsumiya T, Yoshida H et al (2008) Involvement of retinoic acid-inducible gene-I in inflammation of rheumatoid fibroblast-like synoviocytes. Clin Exp Immunol 153:240–244PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Imaizumi T, Tanaka H, Tajima A, Tsuruga K, Oki E, Sashinami H et al (2010) Retinoic acid-inducible gene-I (RIG-I) is induced by IFN-γ in human mesangial cells in culture: possible involvement of RIG-I in the inflammation in lupus nephritis. Lupus 19:830–836PubMedCrossRefGoogle Scholar
  18. 18.
    Tan EM, Cohen AS, Fries JF, Masi AT, Mcshane DJ, Rothfield NF et al (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277PubMedCrossRefGoogle Scholar
  19. 19.
    Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725PubMedCrossRefGoogle Scholar
  20. 20.
    Enevold C, Oturai AB, Sørensen PS, Ryder LP, Koch-Henriksen N, Bendtzen K (2009) Multiple sclerosis and polymorphisms of innate pattern recognition receptors TLR1-10, NOD1-2, DDX58, and IFIH1. J Neuroimmunol Elsevier BV 212: 125–131Google Scholar
  21. 21.
    Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM et al (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29:308–311PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Wigginton JE, Cutler DJ, Abecasis GR (2005) A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 76:887–893PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Harley J, Alarcón-Riquelme M (2008) Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet 40:204–210PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Cunninghame Graham DS, Morris DL, Bhangale TR, Criswell LA, Syvänen A-C, Rönnblom L et al (2011) Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet 7:e1002341PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Cen H, Leng R-X, Wang W, Zhou M, Feng C-C, Zhu Y et al (2013) Association study of IFIH1 rs1990760 polymorphism with systemic lupus erythematosus in a Chinese population. Inflammation 36:444–448PubMedCrossRefGoogle Scholar
  26. 26.
    Robinson T, Kariuki SN, Franek BS, Kumabe M, Kumar AA, Badaracco M et al (2011) Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-α and serologic autoimmunity in lupus patients. J Immunol 187:1298–1303PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Laska MJ, Troldborg A, Hansen B, Stengaard-Pedersen K, Junker P, Nexø BA et al (2014) Polymorphisms within Toll-like receptors are associated with systemic lupus erythematosus in a cohort of Danish females. Rheumatology (Oxford) 53(1):48–55Google Scholar
  28. 28.
    Hu J, Nistal-Villán E, Voho A, Ganee A, Kumar M, Ding Y et al (2010) A common polymorphism in the caspase recruitment domain of RIG-I modifies the innate immune response of human dendritic cells. J Immunol 185:424–432PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Pothlichet J, Burtey A, Kubarenko AV, Caignard G, Solhonne B, Tangy F et al (2009) Study of human RIG-I polymorphisms identifies two variants with an opposite impact on the antiviral immune response. PLoS One 4:e7582PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Bengtsson AA, Sturfelt G, Truedsson L, Blomberg J, Alm G, Vallin H et al (2000) Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies. Lupus 9:664–671PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • C. Enevold
    • 1
  • L. Kjær
    • 1
  • C. H. Nielsen
    • 1
  • A. Voss
    • 3
  • R. S. Jacobsen
    • 1
  • M. L. F. Hermansen
    • 1
  • L. Redder
    • 4
  • A. B. Oturai
    • 2
  • P. E. Jensen
    • 2
  • K. Bendtzen
    • 1
  • S. Jacobsen
    • 1
    • 5
  1. 1.Department of Infectious Diseases and RheumatologyInstitute for Inflammation Research, RigshospitaletCopenhagenDenmark
  2. 2.Department of Neurology, Danish Multiple Sclerosis CenterCopenhagen University Hospital RigshospitaletCopenhagenDenmark
  3. 3.Department of RheumatologyOdense University HospitalOdenseDenmark
  4. 4.Department of Clinical ImmunologyOdense University HospitalOdenseDenmark
  5. 5.Section 4242, Department of Infectious Diseases and RheumatologyRigshospitalet, Copenhagen University HospitalCopenhagenDenmark

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