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The Promoter SNP, but not the Alternative Splicing SNP, is Linked to Multiple Sclerosis Among Jordanian Patients

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Abstract

Multiple sclerosis is a chronic inflammatory autoimmune disease of the human central nervous system. A number of studies with compelling evidence have provided correlation between single nucleotide polymorphisms in interleukin-7 receptor alpha and multiple sclerosis (MS) in several populations. One such variation, rs6897932, is located within the coding region and results in the generation of a soluble receptor, whereas another one, rs11567685, is located in the promoter region and affects gene expression. In this study, we investigated the frequencies of these two SNPs and their association to MS in 200 healthy controls and 200 MS patients based on a simple PCR-RFLP strategy not reported previously. The frequencies of the high risk alleles for both SNPs were in a high range among healthy and MS subjects relative to previous studies. In addition, whereas no association was found between the alternative splicing SNP, rs6897932, and MS, a significant link was found between the promoter SNP, rs11567685, and MS. These results are in contrast to other studies and may have important implications as to the molecular contribution of IL-7Rα in multiple sclerosis.

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References

  • Ahram M, El-Omar A, Baho Y, Lubad MA (2009) Association between human herpes virus 6 and occurrence of multiple sclerosis among Jordanian patients. Acta Neurol Scand 120(6):430–435

    Article  CAS  PubMed  Google Scholar 

  • Akkad DA, Hoffjan S, Petrasch-Parwez E, Beygo J, Gold R, Epplen JT (2009) Variation in the IL7RA and IL2RA genes in German multiple sclerosis patients. J Autoimmun 32:110–115

    Article  CAS  PubMed  Google Scholar 

  • Alcina A, Fedetz M, Ndagire D, Fernandez O, Leyva L, Guerrero M, Arnal C, Delgado C, Matesanz F (2008) The T244I variant of the interleukin-7 receptor-alpha gene and multiple sclerosis. Tissue Antigens 72:158–161

    Article  CAS  PubMed  Google Scholar 

  • al-Din AS, El-Khateeb M, Kurdi A, Mubaidin A, Wriekat A, Al-Shehab A, Khalil RW (1995) Multiple sclerosis in Arabs in Jordan. J Neurol Sci 131:144–149

    Article  CAS  PubMed  Google Scholar 

  • Barcellos LF, Oksenberg JR, Begovich AB, Martin ER, Schmidt S, Vittinghoff E, Goodin DS, Pelletier D, Lincoln RR, Bucher P, Swerdlin A, Pericak-Vance MA, Haines JL, Hauser SL, Multiple Sclerosis Genetics Group (2003) HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 72(3):710–716

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barten LJ, Allington DR, Procacci KA, Rivey MP (2010) New approaches in the management of multiple sclerosis. Drug Des Devel Ther 4:343–366

    CAS  PubMed Central  PubMed  Google Scholar 

  • Booth DR, Arthur AT, Teutsch SM, Bye C, Rubio J, Armati PJ, Pollard JD, Heard RN, Stewart GJ, 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 83(10):822–830

    Article  CAS  PubMed  Google Scholar 

  • Broux B, Hellings N, Venken K, Rummens J, Hensen K, Wijmeersch B, Stinissen P (2010) Haplotype 4 of the multiple sclerosis associated interleukin-7 receptor alpha gene influences the frequency of recent thymic emigrants. Genes Immun 11(4):326–333

    Article  CAS  PubMed  Google Scholar 

  • Compston A, Coles A (2002) Multiple sclerosis. Lancet 359:1221–1231

    Article  PubMed  Google Scholar 

  • El-Salem K, Al-Shimmery E, Horany K, Al-Refai A, Al-Hayk K, Khader Y (2006) Multiple sclerosis in Jordan, a clinical and epidemiological study. J Neurol 253:1210–1216

    Article  PubMed  Google Scholar 

  • Evsyukova I, Jason A, Somarelli J, Simon G, Gregory SG, Blanco M (2010) Alternative splicing in multiple sclerosis and other autoimmune diseases. RNA Biol 7(4):462–473

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fang L, Isobe N, Yoshimura S, Yonekawa T, Matsushita T, Masaki K, Doi H, Ochi K, Miyamoto K, Kawano Y, Kira J (2011) South Japan Multiple Sclerosis Genetics Consortium. Interleukin-7 receptor alpha gene polymorphism influences multiple sclerosis risk in Asians. Neurol 76(24):2125–2127

    Article  CAS  Google Scholar 

  • Gregory S, Schmidt S, Seth P, Oksenberg J, Hart J, Prokop A, Caillier S, Ban M, Goris A, Barcellos L, Lincoln R, McCauley J, Sawcer S, Compston D, Dubois B, Hauser S, Blanco M, Vance M, Haines J (2007) Interleukin 7 receptor a chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 9(39):1083–1091

    Article  Google Scholar 

  • Haas J, Korporal M, Schwarz A, Balint B, Wildemann B (2011) The interleukin-7 receptor a chain contributes to altered homeostasis of regulatory T cells in multiple sclerosis. Europ J Immunol 41:845–853

    Article  CAS  Google Scholar 

  • Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PW, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Simon G, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Stephen L, Hauser SL (2007) Risk alleles for multiple sclerosis identified by a genome-wide study. New Eng J Med 357:851–862

    Article  CAS  PubMed  Google Scholar 

  • Heidari M, Behmanesh M, Sahraian A (2011) Variation in SNPs of the IL7Ra Gene is associated with multiple sclerosis in the Iranian population. Immunol Invest 40(3):279–289

    Article  CAS  PubMed  Google Scholar 

  • Hoe E, McKay FC, Schibeci SD, Gandhi K, Heard RN, Stewart GJ, Booth DR (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):2512–2517

    Article  CAS  PubMed  Google Scholar 

  • Hoffjan S, Akkad DA (2010) The genetics of multiple sclerosis. An update Molec Cell Probes 24:237–243

    Article  CAS  Google Scholar 

  • International Multiple Sclerosis Genetics Consortium; Wellcome Trust Case Control Consortium 2, Sawcer S et al. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–9

    Google Scholar 

  • Jersild C, Svejgaard A, Fog T (1972) HLA antigens and multiple sclerosis. Lancet 1(7762):1240–1241

    Article  CAS  PubMed  Google Scholar 

  • Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, Hintzen RQ (2012a) Decreased systemic IL-7 and soluble IL-7RAα in multiple sclerosis patients. Genes Immun 13(7):587–592

    Article  CAS  PubMed  Google Scholar 

  • Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, Hintzen RQ (2012b) The IL-7RAα pathway is quantitatively and functionally altered in CD8 T cells in multiple sclerosis. J Immunol 188(4):1874–1883

    Article  CAS  PubMed  Google Scholar 

  • Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis, results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurol 46(4):907–911

    Article  CAS  Google Scholar 

  • Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom E, Khademi M, Oturai A, Ryder L, Saarela J, Harbo H, Celius E, Salter H, Olsson T, Hillert J (2007) Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis. Nat Genet 9(39):1108–1113

    Article  Google Scholar 

  • Lundström W, Highfill S, Walsh ST, Beq S, Morse E, Kockum I, Alfredsson L, Olsson T, Hillert J, Mackall CL (2013) Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity. Proc Natl Acad Sci U S A 110(19):E1761–E1770

    Article  PubMed Central  PubMed  Google Scholar 

  • McKay FC, Swain LI, Schibeci SD, Rubio JP, Kilpatrick TJ, Heard RN, Stewart GJ, Booth DR (2008) Haplotypes of the interleukin 7 receptor alpha gene are correlated with altered expression in whole blood cells in multiple sclerosis. Genes Immun 9(1):1–6

    Google Scholar 

  • Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. New Eng J Med 13(343):938–952

    Article  Google Scholar 

  • O’Doherty C, Kantarci O, Vandenbroeck K (2008) IL7RA polymorphisms and susceptibility to multiple sclerosis. New Eng J Med 358:753–754

    Article  PubMed  Google Scholar 

  • Pandit L, Ban M, Sawcer S, Singhal B, Nair S, Radhakrishnan K, Shetty R, Misri Z, Hegde S, Bhat IG (2011) Evaluation of the established non-MHC multiple sclerosis loci in an Indian population. Mult Scler 17(2):139–143

    Article  CAS  PubMed  Google Scholar 

  • Stanković A, Dincić E, Ristić S, Lovrecić L, Starcević CN, Djurić T, Sepcić J, Kapović M, Raicević R, Peterlin B, Alavantić D, Zivković M (2007) Interleukin 7 receptor alpha polymorphism rs6897932 and susceptibility to multiple sclerosis in the Western Balkans. Mult Scler 16(5):533–536

    Article  Google Scholar 

  • Teutsch S, Booth DR, Bennetts BH, Heard R, Stewart G (2003) Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-α gene and their associations with multiple sclerosis. Euro J Hum Genet 11:509–515

    Article  CAS  Google Scholar 

  • Trapp B, Nave K (2008) Multiple sclerosis, an immune or neurodegenerative disorder? Ann Rev Neurosci 31:247–269

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

We would like to offer our gratitude to the MS patients and the staff at the Multiple Sclerosis Society and the Health Insurance Doctorate for their cooperation. Special thanks to the team of the genetics laboratory at The National Center for Diabetes, Endocrinology & Genetics.

Funding

This work was funded by the Faculty of Higher Studies at The University of Jordan.

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Authors and Affiliations

  1. Department of Pathology, Microbiology, and Forensic Medicine, The University of Jordan, Amman, Jordan

    Leena Ibayyan, Rand Zaza & Mohammad El-Khateeb

  2. Department of Internal Medicine, Faculty of Medicine, The University of Jordan, Amman, Jordan

    Said Dahbour & Bilal Samhouri

  3. Al-Bashir Hospital, Amman, Jordan

    Ammar El-Omar

  4. Department of Physiology and Biochemistry, Faculty of Medicine, The University of Jordan, Amman, 11942, Jordan

    Mamoun Ahram

Authors
  1. Leena Ibayyan
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  2. Rand Zaza
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  3. Said Dahbour
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  4. Ammar El-Omar
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  5. Bilal Samhouri
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  6. Mohammad El-Khateeb
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  7. Mamoun Ahram
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Corresponding author

Correspondence to Mamoun Ahram.

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Ibayyan, L., Zaza, R., Dahbour, S. et al. The Promoter SNP, but not the Alternative Splicing SNP, is Linked to Multiple Sclerosis Among Jordanian Patients. J Mol Neurosci 52, 467–472 (2014). https://doi.org/10.1007/s12031-013-0151-0

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  • DOI: https://doi.org/10.1007/s12031-013-0151-0

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