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Rheumatology International

, Volume 39, Issue 1, pp 111–119 | Cite as

Genetic variations in the IL-12B gene in association with IL-23 and IL-12p40 serum levels in ankylosing spondylitis

  • Mariana IvanovaEmail author
  • Irena ManolovaEmail author
  • Lyuba Miteva
  • Rada Gancheva
  • Rumen Stoilov
  • Spaska Stanilova
Genes and Disease
  • 57 Downloads

Abstract

In the present study, we evaluated the implication of IL12Bpro (rs17860508) and IL12B 3′ UTR A/C single nucleotide polymorphisms (SNPs) (rs3212227) for the ankylosing spondylitis (AS) development and the impact of IL12B genetic variations on IL-23 and IL-12p40 production and musculoskeletal disease characteristics. 80 patients with AS and 242 healthy controls were studied. Genotyping for the rs3212227 was performed by restriction fragment length polymorphisms–polymerase chain reaction (PCR) and for the rs17860508 by allele-specific PCR. Cytokines were measured by an enzyme-linked immunosorbent assay (ELISA). Clinical status was evaluated by calculation of the Ankylosing Spondylitis Disease Activity Score (ASDAS) using the C-reactive protein (CRP) level, the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI). An association was found for the rs17860508 polymorphism with AS under the allelic, the dominant, and the co-dominant models. Rs3212227 was not attributable to AS susceptibility by itself, but the carriage of C allele in the genotype amplifies the genetic risk for AS in the carriers of the high-risk IL12Bpro 2-allele, especially in homozygosity. Circulating IL-23 and IL-12p40 were raised among AS patients, as some of the genotypes of both IL12B polymorphisms positively regulate their expression. Carriage of the IL12Bpro genotype 2.2 has been linked to a worsened functional disability, while 3′ UTR CC genotype—with severe disease activity. IL12B polymorphisms can impact AS susceptibility and modulate IL-23 and IL-12p40 production levels, and have a contribution to the disease phenotype.

Keywords

Ankylosing spondylitis Genetic predisposition to disease Cytokines 

Notes

Author contributions

Research concept and design: Mariana Ivanova, Irena Manolova, Spaska Stanilova. Data collection: Mariana Ivanova, Irena Manolova, Lyuba Miteva, Rada Gancheva. Data analysis and interpretation: Irena Manolova, Mariana Ivanova, Lyuba Miteva, Rada Gancheva, Rumen Stoilov, Spaska Stanilova. Writing the article: Mariana Ivanova, Irena Manolova, Critical revision of the article: Spaska Stanilova, Rumen Stoilov.

Funding

This work was supported by the Fund for Scientific and Mobile Project of the Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria; Grant No. 2/2016.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Brewerton DA, Hart FD, Nicholls A, Caffrey M, James DC, Sturrock RD (1973) Ankylosing spondylitis and HL-A27. Lancet 1:904–907CrossRefGoogle Scholar
  2. 2.
    Schlosstein L, Terasaki PI, Bluestone R, Pearson CM (1973) High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 288:704–706CrossRefGoogle Scholar
  3. 3.
    Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J, Wordsworth BP, Cornélis F (1996) HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis 55:268–270CrossRefGoogle Scholar
  4. 4.
    Gran JT, Husby G, Hordvik M (1985) Prevalence of ankylosing spondylitis in males and females in a young middle-aged population of Tromso, northern Norway. Ann Rheum Dis 44:359–367CrossRefGoogle Scholar
  5. 5.
    Braun J, Bollow M, Remlinger G, Eggens U, Rudwaleit M, Distler A, Sieper J (1998) Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum 41:58–67CrossRefGoogle Scholar
  6. 6.
    Wtccc TASC (2007) Association scan of 14,500 nsSNPs in four common diseases identifies variants involved in autoimmunity. Nat Genet 39:1329–1337CrossRefGoogle Scholar
  7. 7.
    Reveille JD, Sims AM, Danoy P et al (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42:123–127CrossRefGoogle Scholar
  8. 8.
    Evans DM, Spencer CC, Pointon JJ et al (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43:761–767CrossRefGoogle Scholar
  9. 9.
    Jethwa H, Bowness P (2016) The interleukin (IL)-23/IL-17 axis in ankylosing spondylitis: new advances and potentials for treatment. Clin Exp Immunol 183:30–36CrossRefGoogle Scholar
  10. 10.
    Costello ME, Elewant D, Kenna JJ, Brown MA (2013) Microbiomes, the gut and ankylosing spondylitis. Arthritis Res Ther 15:214CrossRefGoogle Scholar
  11. 11.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189CrossRefGoogle Scholar
  12. 12.
    Van Eden W, van der Zee R, van Kooten P, Berlo SE, Cobelens PM, Kavelaars A, Heijnen CJ, Prakken B, Roord S, Albani S (2002) Balancing the immune system: Th1 and Th2. Ann Rheum Dis 61:25–28CrossRefGoogle Scholar
  13. 13.
    Zhu J, Yamane H, Paul WE (2010) Differentiation of Effector CD4 T Cell Populations. Annu Rev Immunol 28:445–489CrossRefGoogle Scholar
  14. 14.
    Van der Linden SM, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27:361–368CrossRefGoogle Scholar
  15. 15.
    Lukas C, Landewe R, Sieper J, Dougados M, Davis J, Braun J, van der Linden S, van der Heijde D, for the Assessment of SpondyloArthritis international Society (2009) Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis 68:18–24CrossRefGoogle Scholar
  16. 16.
    Van der Heijde D, Lie E, Kvien TK, Sieper J, Van den Bosch F, Listing J, Braun J, Landewe R, for the Assessment of SpondyloArthritis international Society (ASAS) (2009) ASDAS, a highly discriminatory ASAS-endorsed disease activity score in patients with ankylosing spondylitis. Ann Rheum Dis 68:1811–1818CrossRefGoogle Scholar
  17. 17.
    Machado P, Landewe R, Lie E, Kvien TK, Braun J, Baker D, van der Heijde D, for the Assessment of SpondyloArthritis international Society (2011) Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis 70:47–53CrossRefGoogle Scholar
  18. 18.
    Calin A, Garrett S, Whitelock H, Kennedy LG, O`Hea J, Mallorie P, Jenkinson T (1994) A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 21:2281–2285Google Scholar
  19. 19.
    Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A (1994) Defining spinal mobility in ankylosing spondylitis (AS): the Bath AS metrology index. J Rheumatol 21:1694–1698Google Scholar
  20. 20.
    Miteva L, Manolova I, Ivanova M, Rashkov R, Stoilov R, Gulubova M, Stanilova S (2012) Functional genetic polymorphisms in interleukin-12B gene in association with systemic lupus erythematosus. Rheumatol Int 32:53–59CrossRefGoogle Scholar
  21. 21.
    Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910–1914CrossRefGoogle Scholar
  22. 22.
    Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D’Alfonso S (1999) Cytokine gene polymorphism in human disease: on-line databases. Genes Immun 1:3–19CrossRefGoogle Scholar
  23. 23.
    Van Dyke AL, Cote ML, Wenzlaff AS, Land S, Schwartza AG (2009) Cytokine SNPs: comparison of allele frequencies by race & implications for future studies. Cytokine 46:236–244CrossRefGoogle Scholar
  24. 24.
    Meenagh A, Williams F, Ross OA et al (2002) Frequency of cytokine polymorphisms in populations from Western Europe, Africa, Asia, the Middle East and South America. Hum Immunol 63:1055–1061CrossRefGoogle Scholar
  25. 25.
    Wong RH, Wei JC, Huang CH, Lee HS, Chiou SY, Lin SH, Cai YW, Hung PH, Wang MF, Yang SF (2012) Association of IL-12B genetic polymorphism with the susceptibility and disease severity of ankylosing spondylitis. J Rheumatol 39:135–140CrossRefGoogle Scholar
  26. 26.
    Zhang L, Fan D, Liu L, Yang T, Ding N, Hu Y, Cai G, Wang L, Xin L, Xia Q, Li X, Xu S, Xu J, Yang X, Zou Y, Pan F (2015) Association study of IL-12B polymorphisms susceptibility with ankylosing spondylitis in mainland han population. PLoS One 10(6):e0130982CrossRefGoogle Scholar
  27. 27.
    Filer C, Ho P, Smith RL, Griffiths C, Young HS, Worthington J, Bruce IN, Barton A (2008) Investigation of association of the IL12B and IL23R genes with psoriatic arthritis. Arthritis Rheum 58:3705–3709CrossRefGoogle Scholar
  28. 28.
    Jadon D, Tillett W, Wallis D, Cavill C, Bowes J, Waldron N, Dixon A, Sengupta R, Barton A, Korendowych E, McHugh NJ (2013) Exploring ankylosing spondylitis-associated ERAP1, IL23R and IL12B gene polymorphisms in subphenotypes of psoriatic arthritis. Rheumatology 52:261–266CrossRefGoogle Scholar
  29. 29.
    Li J, Zhang C, Wang JB, Chen SS, Zhang TP, Li S, Pan HF, Ye DQ (2016) Relationship between the IL12B (rs3212227) gene polymorphism and susceptibility to multiple autoimmune diseases: a meta-analysis. Mod Rheumatol 26:749–756CrossRefGoogle Scholar
  30. 30.
    Keller C, Webb A, Davis J (2003) Cytokines in the seronegative spondyloarthropathies and their modification by TNF blockade: a brief report and literature review. Ann Rheum Dis 62:1128–1132CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Clinic of Rheumatology, Medical FacultyUniversity Hospital “St. Ivan Rilski”, Medical UniversitySofiaBulgaria
  2. 2.Department of Molecular Biology, Immunology and Medical Genetics, Medical FacultyTrakia University, 11, Armeiska StStara ZagoraBulgaria

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