Skip to main content

Advertisement

SpringerLink
Log in

Association of interleukin 6, interleukin 7 receptor alpha, and interleukin 12B gene polymorphisms with multiple sclerosis

  • Original Article
  • Published:
Acta Neurologica Belgica Aims and scope Submit manuscript

Abstract

Pro-inflammatory and anti-inflammatory cytokines have been shown to play a crucial role in the pathophysiology of multiple sclerosis (MS). We investigated the association between interleukin (IL) IL6-174 G/C (rs1800795), IL7RA C/T (rs6897932), and IL-12B A1188C (rs3212227) gene polymorphisms (SNPs) and MS. The study consisted of 297 unrelated MS patients and 135 healthy individuals. In IL6-174G/C (rs1800795), a significant association between the C allele and MS risk [OR 1.41, 95% CI (1.05–1.92); P = 0.025] was found. Carriage of genotypes CC and CG were more common in MS patients [OR 1.58, 95% CI (1.04–2.39); P = 0.031] and also in female MS patients [OR 1.68, 95% CI (1.02–2.79); P = 0.043]. However, after applying Bonferroni’s correction the differences did not remain significant. No significant association between the IL7RA C/T (rs6897932) and IL12B A1188C (rs3212227) gene polymorphisms and MS susceptibility was observed. Regarding IL-12B A1188C (rs3212227), a significant association between the CC genotype and MS progression, expressed as MSSS, was demonstrated in the female MS group. Our results indicate that the distribution of IL6-174G/C (rs1800795) SNP was marginally associated with MS susceptibility. We also showed that IL-12B A1188C (rs3212227) can contribute to the progression of the disease in the Czech population.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hartung H, Bar-Or A, Zoukos Y (2004) What do we know about the mechanism of action of disease modifying treatments in MS? J Neurol 251:v12–v19

    Article  PubMed  CAS  Google Scholar 

  2. Trapp BD, Nave KA (2008) Multiple sclerosis: an immune or neurodegenerative disorder? Ann Rev Neurosci 31:247–269

    Article  PubMed  CAS  Google Scholar 

  3. Hauser SL, Goodin DS (2012) Multiple sclerosis and other demyelinating diseases. In: Longo DL, Fauci SA, Kasper DL et al. (eds) Harrison’s principle of internal medicine, vol 18. McGraw-Hill, New York

    Google Scholar 

  4. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8(9):913–919

    Article  PubMed  CAS  Google Scholar 

  5. Sadovnick AD (2012) Genetic background of multiple sclerosis. Autoimmun Rev 11:163–166

    Article  PubMed  CAS  Google Scholar 

  6. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer S, Hellenthal G, Pirinen M et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219

    Article  CAS  Google Scholar 

  7. International Multiple Sclerosis Genetics Consortium (IMSGC), Wellcome Trust Case Control Consortium 2 (WTCCC2), International IBD Genetics Consortium (IIBDGC), Beecham AH et al (2013) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 45:1353–1360

    Article  CAS  Google Scholar 

  8. Jadidi-Niaragh F, Mirshafiey A (2011) Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 74:1–13

    Article  PubMed  CAS  Google Scholar 

  9. Pittock SJ, Lucchinetti CF (2007) The pathology of MS: new insights and potential clinical applications. Neurologist 13:45–56

    Article  PubMed  Google Scholar 

  10. Gaffen SL, Jain R, Garg AV, Cua DJ (2014) The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14:585–600

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Del Vecchio M, Bajetta E, Canova S et al (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677–4685

    Article  PubMed  Google Scholar 

  12. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3:133–146

    Article  PubMed  CAS  Google Scholar 

  13. Bank S, Andersen PS, Burisch J et al (2015) Polymorphisms in the toll-like receptor and the IL-23/IL-17 pathways were associated with susceptibility to inflammatory bowel disease in a Danish cohort. PLoS One 10(12):e0145302. https://doi.org/10.1371/journal.pone.0145302

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Liu Z, Yadav PK, Xu X et al (2011) The increased expression of IL-23 in inflammatory bowel disease promotes intraepithelial and lamina propria lymphocyte inflammatory responses and cytotoxicity. J Leukoc Biol 89:597–606

    Article  PubMed  CAS  Google Scholar 

  15. Zheng Y, Wang M, Tian T et al (2017) Role of interleukin-12 gene polymorphisms in the onset risk of cancer: a meta-analysis. Oncotarget 2:29795–29807

    Google Scholar 

  16. Sun L, He C, Nair L et al (2015) Interleukin 12 (IL-12) family cytokines: role in immune pathogenesis and treatment of CNS autoimmune disease. Cytokine 75:249–255

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Tsunemi Y, Saeki H, Nakamura K et al (2002) Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris. J Dermatol Sci 30:161–166

    Article  PubMed  CAS  Google Scholar 

  18. Wang EY, Yang Q, Liao ZG (2015) Association of polymorphisms in interleukin (IL)-12A and -B genes with rheumatoid arthritis in a Chinese population. Clin Exp Immunol 180:83–89

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Shi X, Jia Y, Xie X et al (2017) Single-nucleotide polymorphisms of the IL-12 gene lead to a higher cancer risk: a meta-analysis based on 22,670 subjects. Genes Genet Syst. https://doi.org/10.1266/ggs.16-00024

    Article  PubMed  Google Scholar 

  20. Gocket AR, Cravens PD, Ben LH et al (2007) T-bet regulaetes the fate of Th1 and Th17 lymphocytes in autoimmunity. J Immunol 178:1341–1348

    Article  Google Scholar 

  21. Yang XO et al (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Frausto RF et al (2009) Site-specific production of IL-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis. J Immunol 183:2079–2088

    Article  PubMed  CAS  Google Scholar 

  23. Rivera-Chavez FA, Peters-Hybki DL, Barber RC, O’Keefe GE (2003) Interleukin-6 promoter haplotypes and interleukin-6 cytokine responses. Shock 20:218–223

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Slattery ML, Wolff RK, Curtin K et al (2009) Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Mutat Res 660:12–21

    Article  PubMed  CAS  Google Scholar 

  25. Tartter M, Hammen C, Bower JE et al (2015) Effects of chronic interpersonal stress exposure on depressive symptoms are moderated by genetic variation at IL6 and IL1β in youth. Brain Behav Immun 46:104–111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Chumaeva N, Hintsanen M, Pulkki-Råback L et al (2014) Interleukin-6 gene polymorphism, chronic stress and atherosclerosis: interleukin-6-174G/C polymorphism, chronic stress and risk of early atherosclerosis in the Cardiovascular Risk in Young Finns study. Psychosom Res 76:333–338

    Article  Google Scholar 

  27. Ururahy MA, de Souza KS, Oliveira YM et al (2015) Association of polymorphisms in IL6 gene promoter region with type 1 diabetes and increased albumin-to-creatinine ratio. Diabetes Metab Res Rev 31:500–506

    Article  PubMed  CAS  Google Scholar 

  28. Durães C, Moreira CS, Alvelos I et al (2014) Polymorphisms in the TNFA and IL6 genes represent risk factors for autoimmune thyroid disease. PloS One 9(8):e105492. https://doi.org/10.1371/journal.pone.0105492

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Mirowska-Guzel D, Gromadzka G, Mach A et al (2011) Association of IL1A, IL1B, ILRN, IL6, IL10 and TNF-α polymorphisms with risk and clinical course of multiple sclerosis in a Polish population. J Neuroimmunol 236:87–92

    Article  PubMed  CAS  Google Scholar 

  30. Ye SK, Agata Y, Lee HC et al (2001) The IL-7 receptor controls the accessibility of the TCRgamma locus by Stat5 and histone acetylation. Immunity 15(5):813–823

    Article  PubMed  CAS  Google Scholar 

  31. Gregory SG, Schmidt S, Seth P, et al, Multiple Sclerosis Genetics Group (2007) Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39:1083–1091

    Article  PubMed  CAS  Google Scholar 

  32. Liu H, Huang J, Dou M et al (2017) Variants in the IL7RA gene confer susceptibility to multiple sclerosis in Caucasians: evidence based on 9734 cases and 10436 controls. Sci Rep 26:1207

    Article  CAS  Google Scholar 

  33. Tavakolpour S, Rahimzadeh G (2016) Interleukin 7 receptor polymorphisms and the risk of multiple sclerosis: a meta-analysis. Scand J Immunol 84:146–149

    Article  PubMed  Google Scholar 

  34. Akkad DA, Hoffjan S, Petrasch-Parwez E et al (2009) Variation in the IL7RA and IL2RA genes in German multiple sclerosis patients. J Autoimmun 32:110–115

    Article  PubMed  CAS  Google Scholar 

  35. Lundmark F, Duvefelt K, Iacobaeus E et al (2007) Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet 39:1108–1113

    Article  PubMed  CAS  Google Scholar 

  36. Compston A, Coles A (2008) Multiple sclerosis. Lancet 25:372:1502–1517

    Article  CAS  Google Scholar 

  37. Polman CH, Reingold SC, Banwell B et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 33:1444–1452

    Article  PubMed  CAS  Google Scholar 

  39. Roxburgh RH, Seaman SR, Masterman T et al (2005) Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology 64:1144–1151

    Article  PubMed  CAS  Google Scholar 

  40. International Multiple Sclerosis Genetics Consortium, Hafler DA et al (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851–862

    Article  Google Scholar 

  41. Nicot A (2009) Gender and sex hormones in multiple sclerosis pathology and therapy. Front Biosci 14:4477–4515

    Article  CAS  Google Scholar 

  42. Kikuchi S, Fukazawa T, Niino M et al (2002) Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients: interaction with HLA-DRB1*1501 and disease modulation. J Neuroimmunol 128(1–2):77–81

    Article  PubMed  CAS  Google Scholar 

  43. Benešová Y, Vašků A, Štourač P et al (2013) Association of HLA-DRB1*1501 tagging rs3135388 gene polymorphism with multiple sclerosis. J Neuroimmunol 255(1–2):92–96

    Article  PubMed  CAS  Google Scholar 

  44. Čierny D, Hányšová S, Michalik J et al (2015) Genetic variants in interleukin 7 receptor α chain (IL-7Rα) are associated with multiple sclerosis risk and disability progression in Central European Slovak population. J Neuroimmunol 282:80–84

    Article  PubMed  CAS  Google Scholar 

  45. Weber F, Fontaine B, Cournu-Rebeix I et al (2008) IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun 9:259–263

    Article  PubMed  CAS  Google Scholar 

  46. Zhang Z, Duvefelt K, Svensson F et al (2005) Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun 6:145–152

    Article  PubMed  CAS  Google Scholar 

  47. Traggiai E, Biagioli T, Rosati E et al (2001) IL-7 enhanced T-cell response to myelin proteins in multiple sclerosis. J Neuroimmunol 121:111–119

    Article  PubMed  CAS  Google Scholar 

  48. Jäger J, Schulze C, Rösner S, Martin R (2013) IL7RA haplotype-associated alterations in cellular immune function and gene expression patterns in multiple sclerosis. Genes Immun 14:453–461

    Article  PubMed  CAS  Google Scholar 

  49. Traboulsee AL, Bernales CQ, Ross JP et al (2014) Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression. Neurogenetics 15:165–169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Zuvich RL, McCauley JL, Oksenberg JR, International Multiple Sclerosis Genetics Consortium, Aubin C, Cross AH, Piccio L et al (2010) Genetic variation in the IL7RA/IL7 pathway increases multiple sclerosis susceptibility. Hum Genet 127:525–535

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Mihailova S, Ivanova M, Mihaylova A et al (2005) Pro- and anti-infalmmatory cytokine gene polymorphism profiles in Bulgarian multiple sclerosis patients. J Neuroimmunol 168:138–143

    Article  PubMed  CAS  Google Scholar 

  52. Shahbazi M, Ebadi H, Fathi D et al (2010) HLA-DRB1*1501 intensifies the impact of IL-6 promoter polymorphism on the susceptibility to multiple sclerosis in an Iranian population. Mult Scler 16:1173–1176

    Article  PubMed  CAS  Google Scholar 

  53. Ewald L, Beate LW, Stephanie S et al (2015) Analysis of a functional IL-6 gene polymorphism in HLAB27 associated and intermediate uveitis gives new insight in disease pathogenesis and commonality with other autoimmune diseases. J Immunol Res. https://doi.org/10.1155/2015/174062

    Article  PubMed  PubMed Central  Google Scholar 

  54. Schönrock LM, Gawlowski G, Brück W (2000) Interleukin-6 expression in human multiple sclerosis lesions. Neurosci Lett 10:45–48

    Article  Google Scholar 

  55. Schulte-Herbrüggen O, Nassenstein C, Lommatzsch M et al (2005) Tumor necrosis factor-alpha and interleukin-6 regulate secretion of brain-derived neurotrophic factor in human monocytes. J Neuroimmunol 160:204–209

    Article  PubMed  CAS  Google Scholar 

  56. Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40:1830–1835

    Article  PubMed  CAS  Google Scholar 

  57. Huang J, Yang Y, Zhou F et al (2016) Meta-analysis of the IL23R and IL12B polymorphisms in multiple sclerosis. Int J Neurosci 126:205–212

    Article  PubMed  CAS  Google Scholar 

  58. Javan MR, Shahraki S, Safa A et al (2017) An interleukin 12 B single nucleotide polymorphism increases IL-12p40 production and is associated with increased disease susceptibility in patients with relapsing–remitting multiple sclerosis. Neurol Res 39:4 35–441

    Article  CAS  Google Scholar 

  59. Liu M, Hu X, Wang Y et al (2014) Association of IL-23 and its receptor gene single-nucleotide polymorphisms with multiple sclerosis in Chinese southern population. Int J Neurosci 124:904–907

    Article  PubMed  CAS  Google Scholar 

  60. Cordell HJ, Clayton DG (2005) Genetic association studies. Lancet 366:1121–1131

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 65269705 (University Hospital Brno, Brno, Czech Republic) [MZ ČR-RVO (FNBr, 65269705)] and by the project “Genetická a epigenetická patofyziologie vybraných stavů”, number 1426/2015 with the support of the Specific University Research Grant, as provided by the Ministry of Education, Youth and Sports of the Czech Republic in the year 2015 and 2016. The authors would like to thank the laboratory personnel of the Department of Pathological Physiology, Faculty of Medicine Masaryk University, Brno. Ethical approval for the study was granted by the institutional ethical committee.

Author information

Authors and Affiliations

  1. Department of Neurology, University Hospital Brno and Faculty of Medicine, Masaryk University, Jihlavská 20, 625 00, Brno, Czech Republic

    Yvonne Benešová

  2. Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Anna Vašků & Julie Bienertová-Vašků

Authors
  1. Yvonne Benešová
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Vašků
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julie Bienertová-Vašků
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yvonne Benešová.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interests.

Ethical approval

The study was approved by the Ethics Committee of Faculty of Medicine, Masaryk University Brno and all procedures were performed in accordance with the Helsinki Declaration as revised in 2013.

Informed consent

Written informed consent was obtained from all subjects.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 47 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Benešová, Y., Vašků, A. & Bienertová-Vašků, J. Association of interleukin 6, interleukin 7 receptor alpha, and interleukin 12B gene polymorphisms with multiple sclerosis. Acta Neurol Belg 118, 493–501 (2018). https://doi.org/10.1007/s13760-018-0994-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13760-018-0994-9

Keywords

Search

Navigation