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Rheumatology International

, Volume 32, Issue 1, pp 53–59 | Cite as

Functional genetic polymorphisms in interleukin-12B gene in association with systemic lupus erythematosus

  • Lyuba D. MitevaEmail author
  • Irena M. Manolova
  • Mariana G. Ivanova
  • Rasho K. Rashkov
  • Rumen M. Stoilov
  • Maya V. Gulubova
  • Spaska A. Stanilova
Original Article

Abstract

Genetic polymorphisms in cytokine genes, which influence gene expression, may have an important impact on SLE susceptibility and severity. The aim of this study was to examine the possible influence of two functional polymorphisms in cis-regulatory regions of IL12B gene in the susceptibility and clinical symptoms of SLE in Bulgarian patients. Female SLE patients (n = 141) and 124 healthy women were included in the study. Genotyping for the IL12B A/C polymorphism in 3′UTR was performed by restriction fragment length polymorphisms PCR assay and for the IL12Bpro polymorphism by allele-specific PCR. Genotype-22 of IL12Bpro polymorphism was overrepresented among women with SLE (28 vs. 17%; OR = 1.875; 95% CI: 1.037 ÷ 3.390; P = 0.037). Respectively, a higher frequency of allele-2 was found in patients than in controls (51% vs. 40%; OR = 1.566; 95% CI: 1.110 ÷ 2.210; P = 0.011). Also, we found significantly elevated frequency of genotype-22 of IL12Bpro polymorphism among SLE patients who were simultaneously carrier of genotype-AA of SNP in 3′UTR. Women with both homozygous genotypes, genotype-AA of SNP in 3′UTR and genotype-22 of IL12Bpro polymorphism, had a 2.1-fold significantly elevated risk for SLE development. The carrying of genotype-11 of IL12Bpro polymorphism was positively associated with hematological and neuropsychiatric manifestations of SLE. We have provided evidence that the IL12Bpro polymorphism was associated with SLE development among Bulgarian women. Although a strong individual effect of SNP in 3′UTR of IL12B was not detected, we found that genotype-22 of IL12Bpro was predominantly combined with genotype-AA of SNP in 3′UTR among SLE patients and this combination elevates the risk of SLE.

Keywords

IL12B Gene polymorphism Systemic lupus erythematosus 

References

  1. 1.
    Magnusson V, Nakken B, Bolstad AI, Alarcón-Riquelme ME (2001) Cytokine polymorphisms in systemic lupus erythematosus and Sjögren’s syndrome. Scand J Immunol 54:55–61. doi: 10.1046/j.1365-3083.2001.00965.x PubMedGoogle Scholar
  2. 2.
    Hollegaard MV, Bidwell JL (2006) Cytokine gene polymorphism in human disease: on-line databases, supplement 3. Genes Immun 7:269–276. doi: 10.1038/sj.gene.6364301 PubMedGoogle Scholar
  3. 3.
    Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146. doi: 10.1038/nri1001 PubMedGoogle Scholar
  4. 4.
    Holscher C (2004) The power of combinatorial immunology: IL-12 and IL-12-related dimeric cytokines in infectious diseases. Med Microbiol Immunol 193:1–17. doi: 10.1007/s00430-003-0186-x PubMedGoogle Scholar
  5. 5.
    Cooper AM, Khader SA (2007) IL-12p40 an inherently agonistic cytokine. Trends Immunol 28:33–38. doi: 10.1016/j.it.2006.11.002 PubMedGoogle Scholar
  6. 6.
    Lauwerys BR, Van Snick J, Houssiau FA (2002) Serum IL-12 in systemic lupus erythematosus: absence of p70 heterodimers but presence of p40 monomers correlating with disease activity. Lupus 11:384–387. doi: 10.1191/0961203302lu213oa PubMedGoogle Scholar
  7. 7.
    Liu TF, Jones BM, Wong RW, Srivastava G (1999) Impaired production of IL-12 in systemic lupus erythematosus III deficient IL-12 p40 gene expression and cross-regulation of IL-12, IL-10 and IFN-gamma gene expression. Cytokine 11:805–811. doi: 10.1006/cyto.1999.0512 PubMedGoogle Scholar
  8. 8.
    Ivanova M, Manolova I, Stoilov R (2005) An elevated level of the circulating interleukin (IL)-12 in systemic lupus erythematosus. Rheumatology 13:79–82Google Scholar
  9. 9.
    Huang X, Hua J, Shen N, Chen S (2007) Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients. Mod Rheumatol 17:220–223. doi: 10.1007/s10165-007-0568-9 PubMedGoogle Scholar
  10. 10.
    Morahan G, Huang D, Ymer SI, Cancilla MR, Stephen K, Dabadghao P, Werther G, Tait BD, Harrison LC, Colman PG (2001) Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nat Genet 27:218–221. doi: 10.1038/84872 PubMedGoogle Scholar
  11. 11.
    Morahan G, Huang D, Wu M, Holt BJ, White GP, Kendall GE, Sly PD, Holt PG (2002) Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet 360:455–459. doi: 10.1016/S0140-6736(02)09676-9 PubMedGoogle Scholar
  12. 12.
    Zwiers A, Seegers D, Heijmans R, Koch A, Hampe J, Nikolaus S, Peña AS, Schreiber S, Bouma G (2004) Definition of polymorphisms and haplotypes in the interleukin-12B gene: association with IL-12 production but not with Crohn’s disease. Genes Immun 5:675–677. doi: 10.1038/sj.gene.6364131 PubMedGoogle Scholar
  13. 13.
    Muller-Berghaus J, Kern K, Paschen A, Nguyen XD, Kluter H, Morahan G, Schadendorf D (2004) Deficient IL-12p70 secretion by dendritic cells based on IL12B promoter genotype. Genes Immun 5:431–434. doi: 10.1038/sj.gene.6364102 PubMedGoogle Scholar
  14. 14.
    Seegers D, Zwiers A, Strober W, Pena AS, Bouma GA (2002) TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 3:419–423. doi: 10.1038/sj.gene.6363919 PubMedGoogle Scholar
  15. 15.
    Stanilova S, Miteva L (2005) Taq-I polymorphism in 3′UTR of the IL-12 and association with IL-12p40 production from human PBMC. Genes Immun 6:364–366. doi: 10.1038/sj.gene.6364213 PubMedGoogle Scholar
  16. 16.
    Nistico L, Giorgi G, Giordano M, Galgani A, Petrone A, D’Alfonso S, Federici M, Di Mario U, Pozzilli P, Buzzetti R, Cascino I (2002) IL12B polymorphism and type 1 diabetes in the Italian population: a case-control study. Diabetes 51:1649–1650. doi: 10.2337/diabetes.51.5.1649 PubMedGoogle Scholar
  17. 17.
    Hirota T, Suzuki Y, Hasegawa K, Obara K, Matsuda A, Akahoshi M, Nakashima K, Cheng L, Takahashi N, Shimizu M, Doi S, Fujita K, Enomoto T, Ebisawa M, Yoshihara S, Nakamura Y, Kishi F, Shirakawa T, Tamari M (2005) Functional haplotypes of IL-12B are associated with childhood atopic asthma. J Allergy Clin Immunol 116:789–795. doi: 10.1016/j.jaci.2005.06.010 PubMedGoogle Scholar
  18. 18.
    Sánchez E, Morales S, Paco L, López-Nevot MA, Hidalgo C, Jiménez-Alonso J, Torres B, González-Gay MA, Callejas JL, Ortego-Centeno N, Sánchez-Roman J, González-Escribano MF, Martín J (2005) Interleukin 12 (IL12B), interleukin 12 receptor (IL12RB1) and interleukin 23 (IL23A) gene polymorphism in systemic lupus erythematosus. Rheumatology 44:1136–1139. doi: 10.1093/rheumatology/keh697 PubMedGoogle Scholar
  19. 19.
    Hirankarn N, Tangwattanachuleeporn M, Wongpiyabovorn J, Wongchinsri J, Avihingsanon Y (2009) Association of IL-18 gene polymorphism (−137C) with arthritis manifestations in SLE: combined effect with IFN gamma gene polymorphism (+874A). Clin Rheumatol 28:219–223. doi: 10.1007/s10067-008-1036-4 PubMedGoogle Scholar
  20. 20.
    Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277PubMedGoogle Scholar
  21. 21.
    Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 35:630–640PubMedGoogle Scholar
  22. 22.
    Stanilova S, Miteva L, Prakova G (2008) IL-12Bpro and GSTP1 polymorphisms in association with silicosis. Tissue Antigens 71:169–174. doi: 10.1111/j.1399-0039.2007.00985.x PubMedGoogle Scholar
  23. 23.
    Miteva L, Stanilov N, Deliysky T, Mintchev N, Stanilova S (2009) Association of polymorphisms in regulatory regions of interleukin-12p40 gene and cytokine serum level with colorectal cancer. Cancer Invest 27:924–931. doi: 10.3109/07357900902918486 PubMedGoogle Scholar
  24. 24.
    Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW (2008) Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol 127:385–393. doi: 10.1016/j.clim.2008.01.019 PubMedGoogle Scholar
  25. 25.
    Peng JC, Abu Bakar S, Richardson M, Jonsson JJ, Frazer IH, Nielsen LK, Morahan G, Thomas R (2006) IL10 and IL12B polymorphisms each influence IL-12p70 secretion by dendritic cells in response to LPS. Immunol Cell Biol 84:227–232. doi: 10.1111/j.1440-1711.2006.01419.x PubMedGoogle Scholar
  26. 26.
    Morahan G, Kaur G, Singh M, Rapthap CC, Kumar N, Katoch K, Mehra NK, Huang D (2007) Association of variants in the IL12B gene with leprosy and tuberculosis. Tissue Antigens 69:234–236. doi: 10.1111/j.1399-0039.2006.773_3.x PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Lyuba D. Miteva
    • 1
    Email author
  • Irena M. Manolova
    • 2
  • Mariana G. Ivanova
    • 3
  • Rasho K. Rashkov
    • 3
  • Rumen M. Stoilov
    • 3
  • Maya V. Gulubova
    • 4
  • Spaska A. Stanilova
    • 1
  1. 1.Medical Faculty, Department of Molecular Biology, Immunology and Medical GeneticsTrakia UniversityStara ZagoraBulgaria
  2. 2.Medical Faculty, Laboratory of Clinical Immunology, University HospitalTrakia UniversityStara ZagoraBulgaria
  3. 3.Clinic of RheumatologyUniversity Hospital, Medical AcademySofiaBulgaria
  4. 4.Medical Faculty, Department of General and Clinical PathologyTrakia UniversityStara ZagoraBulgaria

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