Advertisement

Journal of Molecular Neuroscience

, Volume 67, Issue 1, pp 38–47 | Cite as

Association Between IL7R Promoter Polymorphisms and Multiple Sclerosis in Turkish Population

  • Hasan Simsek
  • Hikmet Geckin
  • Nilay Padir Sensoz
  • Edward O. List
  • Ahmet ArmanEmail author
Article
  • 38 Downloads

Abstract

Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease that affects myelin fibers within the central nervous system resulting in neurological impairment. Although the etiology of MS is not fully understood, environmental and genetic factors are thought to play important roles. IL7R gene polymorphisms which are associated with several autoimmune diseases have also been implicated as a genetic factor for MS following genome-wide association studies. To further examine this association, we investigated the association between MS and IL7R gene − 449 (A/G), − 504 (T/C), and − 1085 (G/T) promoter polymorphisms in Turkish population. Three hundred sixty-four MS patients and 191 healthy controls were involved in this study. Three polymorphic regions in the promoter of IL7R were identified and these regions were amplified by appropriate primers. The PCR products were digested by PstI enzyme for − 504 (T/C) SNP and HphI enzyme for − 1085 (G/T) and − 449 (A/G) SNPs and genotyping was done based on digested PCR product sizes. Genotype distributions and allele frequencies of − 449 polymorphism did not show any significant association with MS directly (p = 0.120 and p = 0.490, respectively). But the genotypes of IL7R − 449 GA for AOMS and AA for EOMS were a risk factor in according to age of onset (p = 0.002, OR = 4.021, 95% CI = 1.642–9.845). Furthermore, IL7R − 449 A allele was found to be a risk factor for EOMS (p = 0.011, OR = 1.3, 95% CI = 1.107–1.527). Significant association was seen between IL7R − 504 TC heterozygote genotype and MS (p = 0.02, OR = 1.702, 95% CI = 1.169–2.478). The IL7R − 1085 (G/T) polymorphism did not show association with MS; however, the haplotype of ACG may be susceptibility to MS and RRMS (p = 0.035, OR = 1.349, 95% CI = 1.020–1.785, and p = 0.041, OR = 1.368, 95% CI = 1.012–1.850, respectively) and the haplotypes of ACG, ATT, and GTG demonstrate a protective effect in EOMS (p = 0.008, OR = 0.326, 95% CI = 0.136–0.782, p = 0.012 and p = 0.012, OR = 0.462, 95% CI = 0.249–0.859, respectively). RRMS frequency in the Turkish population was decreased and SPMS frequency was strongly increased based on comparison to results from other populations. Furthermore, male patients had an increased frequency of SPMS significantly (p = 0.033, OR = 1.667, 95% CI = 1.036–2.682). In conclusion, this is the first study to show a significant association between the IL7R promoter polymorphisms and the age of onset of MS.

Keywords

IL7R Polymorphism Multiple sclerosis Inflammation 

Notes

Acknowledgements

We thank our patients and healthy controls for blood donations.

Funding Information

This study was supported by Marmara University, Scientific Research Projects Committee.

Compliance with Ethical Standards

Research for multiple sclerosis was approved by the Ethics Committee of Marmara University School of Medicine Istanbul, Turkey. All participants had signed an informed consent form before participating.

Competing Interests

The authors declare that they have no competing interests.

References

  1. Albert PR (2011) What is a functional genetic polymorphism? Defining classes of functionality. J Psychiatry Neurosci 36(6):363–365PubMedPubMedCentralGoogle Scholar
  2. Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F, Radue EW, Lindberg RLP, Uitdehaag BMG, Johnson MR, Angelakopoulou A, Hall L, Richardson JC, Prinjha RK, Gass A, Geurts JJG, Kragt J, Sombekke M, Vrenken H, Qualley P, Lincoln RR, Gomez R, Caillier SJ, George MF, Mousavi H, Guerrero R, Okuda DT, Cree BAC, Green AJ, Waubant E, Goodin DS, Pelletier D, Matthews PM, Hauser SL, Kappos L, Polman CH, Oksenberg JR (2009) Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 18(4):767–778PubMedGoogle Scholar
  3. Bashinskaya VV, Kulakova OG, Boyko AN, Favorov AV, Favorova OO (2015) A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches. Hum Genet 134(11–12):1143–1162PubMedGoogle Scholar
  4. Booth DR, Arthur AT, Teutsch SM, Bye C, Rubio J, Armati PJ, Pollard JD, Heard RNS, Stewart GJ, The Southern MS Genetics Consortium (2005) Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis. J Mol Med (Berl) 83(10):822–830Google Scholar
  5. Breij EC, Brink BP, Veerhuis R, van den Berg C, Vloet R, Yan R et al (2008) Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 63(1):16–25PubMedGoogle Scholar
  6. Broux B, Hellings N, Venken K, Rummens J-L, Hensen K, Van Wijmeersch B et al (2010) Haplotype 4 of the multiple sclerosis-associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants. Genes Immun 11(4):326–333PubMedGoogle Scholar
  7. Calzascia T, Pellegrini M, Lin A, Garza KM, Elford AR, Shahinian A, Ohashi PS, Mak TW (2008) CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci U S A 105(8):2999–3004PubMedPubMedCentralGoogle Scholar
  8. Consortium IMSG, 2 WTCCC (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–219Google Scholar
  9. Corfe SA, Paige CJ (2012) The many roles of IL-7 in B cell development; mediator of survival, proliferation and differentiation. Semin Immunol 24(3):198–208PubMedGoogle Scholar
  10. Debouverie M (2009) Gender as a prognostic factor and its impact on the incidence of multiple sclerosis in Lorraine, France. J Neurol Sci 286(1–2):14–17PubMedGoogle Scholar
  11. Ebers GC, Sadovnick AD, Risch NJ (1995) A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature 377(6545):150–151PubMedGoogle Scholar
  12. Evsyukova I, Somarelli JA, Gregory SG, Garcia-Blanco MA (2010) Alternative splicing in multiple sclerosis and other autoimmune diseases. RNA Biol 7(4):462–473PubMedPubMedCentralGoogle Scholar
  13. Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120(Pt 3):393–399PubMedGoogle Scholar
  14. Ghezzi A, Deplano V, Faroni J, Grasso MG, Liguori M, Marrosu G, Pozzilli C, Simone IL, Zaffaroni M (1997) Multiple sclerosis in childhood: clinical features of 149 cases. Mult Scler 3(1):43–46PubMedGoogle Scholar
  15. Gold SM, Voskuhl RR (2009) Estrogen and testosterone therapies in multiple sclerosis. Prog Brain Res 175:239–251PubMedPubMedCentralGoogle Scholar
  16. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley J, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL, Multiple Sclerosis Genetics Group (2007) Interleukin 7 receptor a chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 39(9):1083–1091PubMedGoogle Scholar
  17. Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, Kim SY, Na R, Hennighausen L, Kurtulus S, Erman B, Matzinger P, Merchant MS, Mackall CL (2009) Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol 10(2):149–157PubMedPubMedCentralGoogle Scholar
  18. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL et al (2007) Risk alleles for multiple sclerosis identified by a genome wide study. N Engl J Med 357(9):851–862PubMedGoogle Scholar
  19. Haj MS, Nikravesh A, Kakhki MP, Rakhshi N (2015) Association study of four polymorphisms in the interleukin-7 receptor alpha gene with multiple sclerosis in eastern Iran. Iran J Basic Med Sci 18(6):593–598PubMedPubMedCentralGoogle Scholar
  20. Hauser SL, Oksenberg JR (2006) The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52(1):61–76PubMedGoogle Scholar
  21. He R, Geha RS (2010) Thymic stromal lymphopoietin. Ann N Y Acad Sci 1183:13–24PubMedPubMedCentralGoogle Scholar
  22. Hoe E, McKay FC, Schibeci SD, Gandhi K, Heard RN, Stewart GJ et al (2010) Functionally significant differences in expression of disease-associated IL-7 receptor alpha haplotypes in CD4 T cells and dendritic cells. J Immunol 184(5):2512–2517PubMedGoogle Scholar
  23. Hoffjan S, Akkad DA (2010) The genetics of multiple sclerosis: an update 2010. Mol Cell Probes 24(5):237–243PubMedGoogle Scholar
  24. Hurwitz BJ (2009) The diagnosis of multiple sclerosis and the clinical subtypes. Ann Indian Acad Neurol 12(4):226–230PubMedPubMedCentralGoogle Scholar
  25. Ibayyan L, Zaza R, Dahbour S, El-Omar A, Samhouri B, El-Khateeb M et al (2014) The promoter SNP, but not the alternative splicing SNP, is linked to multiple sclerosis among Jordanian patients. J Mol Neurosci 52(4):467–472PubMedGoogle Scholar
  26. Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD et al (2012) The IL-7Ralpha pathway is quantitatively and functionally altered in CD8 T cells in multiple sclerosis. J Immunol 188(4):1874–1883PubMedGoogle Scholar
  27. Li Z, Zhang Z, He Z, Tang W, Li T, Zeng Z, He L, Shi Y (2009) A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn). Cell Res 19(4):519–523PubMedGoogle Scholar
  28. Liguori M, Marrosu MG, Pugliatti M, Giuliani F, De Robertis F, Cocco E et al (2000) Age at onset in multiple sclerosis. Neurol Sci 21(4 Suppl 2):S825–S829PubMedGoogle Scholar
  29. Lublin FD, Reingold SC (1997) Guidelines for clinical trials of new therapeutic agents in multiple sclerosis: relations between study investigators, advisors, and sponsors. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 48(3):572–574PubMedGoogle Scholar
  30. Lundmark F, Duvefelt K, Hillert J (2007a) Genetic association analysis of the interleukin 7 gene (IL7) in multiple sclerosis. J Neuroimmunol 192(1–2):171–173PubMedGoogle Scholar
  31. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom E, Khademi M et al (2007b) Variation in interleukin 7 receptor a chain (IL7R) influences risk of multiple sclerosis. Nat Genet 39(9):1108–1113PubMedGoogle Scholar
  32. Lundstrom W, Fewkes NM, Mackall CL (2012) IL-7 in human health and disease. Semin Immunol 24(3):218–224PubMedPubMedCentralGoogle Scholar
  33. Lundstrom W, Highfill S, Walsh ST, Beq S, Morse E, Kockum I et al (2013) Soluble IL7Ralpha potentiates IL-7 bioactivity and promotes autoimmunity. Proc Natl Acad Sci U S A 110(19):E1761–E1770PubMedPubMedCentralGoogle Scholar
  34. Martinelli V, Rodegher M, Moiola L, Comi G (2004) Late onset multiple sclerosis: clinical characteristics, prognostic factors and differential diagnosis. Neurol Sci 25(Suppl 4):S350–S355PubMedGoogle Scholar
  35. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 50(1):121–127PubMedGoogle Scholar
  36. McHugh RS, Shevach EM (2002) Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol 168(12):5979–5983PubMedGoogle Scholar
  37. Multiple Sclerosis Overview. 2006 [Updated 2010 May 11]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1316/
  38. Multiple sclerosis: natural history and disease courses. 2013. Available from: http://www.healthline.com/health/multiple-sclerosis/multiple-sclerosis-disease-courses#1.
  39. Mumford CJ, Wood NW, Kellar-Wood H, Thorpe JW, Miller DH, Compston DA (1994) The British Isles survey of multiple sclerosis in twins. Neurology 44(1):11–15PubMedGoogle Scholar
  40. Oksenberg JR, Barcellos LF, Cree BA, Baranzini SE, Bugawan TL, Khan O et al (2004) Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 74(1):160–167PubMedGoogle Scholar
  41. Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL (2008) The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 9(7):516–526PubMedGoogle Scholar
  42. Pohl D, Rostasy K, Jacobi C, Lange P, Nau R, Krone B, Hanefeld F (2009) Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis. J Neurol 257(2):212–216PubMedPubMedCentralGoogle Scholar
  43. Polliack ML, Barak Y, Achiron A (2001) Late-onset multiple sclerosis. J Am Geriatr Soc 49(2):168–171PubMedGoogle Scholar
  44. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302PubMedPubMedCentralGoogle Scholar
  45. Puel A, Ziegler SF, Buckley RH, Leonard WJ (1998) Defective IL7R expression in T(−)B(+)NK(+) severe combined immunodeficiency. Nat Genet 20(4):394–397PubMedGoogle Scholar
  46. Rosati G (2001) The prevalence of multiple sclerosis in the world: an update. Neurol Sci 22(2):117–139PubMedGoogle Scholar
  47. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989PubMedPubMedCentralGoogle Scholar
  48. Stuve O, Oksenberg J (1993) Multiple Sclerosis Overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH et al (eds) GeneReviews(R). University of Washington, Seattle University of Washington, Seattle. All rights reserved, Seattle (WA)Google Scholar
  49. Teutsch SM, Booth DR, Bennetts BH, Heard RN, Stewart GJ (2003) Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis. Eur J Hum Genet 11(7):509–515PubMedGoogle Scholar
  50. van Waesberghe JH, Kamphorst W, De Groot CJ, van Walderveen MA, Castelijns JA, Ravid R et al (1999) Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 46(5):747–754PubMedGoogle Scholar
  51. Wallin MT, Page WF, Kurtzke JF (2004) Multiple sclerosis in US veterans of the Vietnam era and later military service: race, sex, and geography. Ann Neurol 55(1):65–71PubMedGoogle Scholar
  52. Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, Tritapoe J, Hixon JA, Silveira AB, Cardoso BA, Sarmento LM, Correia N, Toribio ML, Kobarg J, Horstmann M, Pieters R, Brandalise SR, Ferrando AA, Meijerink JP, Durum SK, Yunes JA, Barata JT (2011) Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet 43(10):932–939PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical Genetics, School of MedicineMarmara UniversityIstanbulTurkey
  2. 2.Department of Molecular Biology and GeneticsInonu UniversityMalatyaTurkey
  3. 3.Clinics of NeurologyKartal Lutfi Kirdar Research and Training HospitalIstanbulTurkey
  4. 4.The Edison Biotechnology InstituteOhio UniversityAthensUSA
  5. 5.Department of Medical Genetics, Marmara Teaching and Research HospitalMarmara UniversityIstanbulTurkey

Personalised recommendations