Interleukin 7 Receptor Alpha Gene Variants Are Correlated with Gene Expression in Patients with Relapsing-remitting Multiple Sclerosis
-
Arezou Sayad
,
Mir Davood Omrani
,
Ghasem Solgi
,
Rezvan Noroozi
,
Shahram Arsang-Jang
,
Hidetoshi Inoko
,
Mohammad Taheri
Abstract
The association of single nucleotide polymorphisms (SNPs) of the IL-7Rα gene with multiple sclerosis (MS) have been documented in various populations. This study aimed to evaluate the genotype distributions of two SNPs, rs6897932 and rs201084372, and the functional association of rs6897932 in relation to IL-7Rα gene expression in a group of Iranian relapsing-remitting MS (RRMS) patients. Genotyping for both SNPs in the IL7Rα gene and relative quantification of mRNA expression for both isoforms of IL-7Rα were performed in 100 RRMS patients and 100 ethnic-matched healthy controls. Higher significant frequencies of the T allele and TT genotype for rs6897932 (C/T) were observed in patients comparing to controls (p=0.006). Higher frequencies of the T allele and the TT and TG genotypes and lower frequencies of the G allele and GG genotypes for rs201084372 (G/A) were found in patients comparing to controls (p<0.0001). A decreased level of mRNA expression for the membrane-bound IL-7Rα (mbIL-7Rα) and an increased level of mRNA for the soluble IL-7Rα (sIL-7Rα) were observed in patients versus controls (p=0.005 and p=0.002 respectively). A significant decreased level of mRNA expression for mbIL-7Rα (p=0.01) and an increased level of mRNA for sIL-7Rα (p=0.008) were observed in RRMS patients compared to healthy controls carrying the TT+CT genotypes. The higher levels of mRNA expression for the sIL-7Rα isoform in MS patients carrying the IL7R*TT genotype is a new finding not previously reported in studies on the genotype-induced effects of IL-7Rα expression in multiple sclerosis.
1. Robertson NP, O'riordan JI, Chataway J, Kingsley DP, Miller DH, Clayton D, et al. Offspring recurrence rates and clinical characteristics of conjugal multiple sclerosis. Lancet 1997; 349(9065):1587-90.
2. Sadovnick A D, Traboulsee A L, Zhao Y, Bernales C Q, Encarnacion M, Ross J P, Vilariño-Güell C. Genetic modifiers of multiple sclerosis progression, severity and onset. Clinical Immunology (2017); 180:100-5.
3. Tajouri L, Fernandez F, Griffiths LR. Gene expression studies in multiple sclerosis. Curr Genomics 2007; 8(3):181-9.
4. Eftekharian MM, Ghannad MS, Taheri M, Roshanaei G, Mazdeh M, Musavi M, et al. Frequency of viral infections and environmental factors in multiple sclerosis. Hum Antibodies 2016; 24(1-2):17-23.
5. Martin R, Bielekova B, Hohlfeld R, Utz U. Biomarkers in multiple sclerosis. Dis Markers 2006; 22(4):183-5.
6. Mazdeh M, Taheri M, Sayad A, Bahram S, Omrani
MD, Movafagh A, et al. HLA genes as modifiers of response to IFN-β-1a therapy in relapsing-remitting multiple sclerosis. Pharmacogenomics 2016; 17(5):489-98.
7. Stinissen P, Hellings N. Activation of myelin reactive T cells in multiple sclerosis: a possible role for T cell degeneracy? Eur J Immunol 2008; 38(5):1190-3.
8. Bielekova B, Muraro PA, Golestaneh L, Pascal J, McFarland HF, Martin R. Preferential expansion of autoreactive T lymphocytes from the memory T-cell pool by IL-7. J Neuroimmunol 1999; 100(1):115-23.
9. Fry TJ, Mackall CL. Interleukin-7: from bench to clinic. Blood 2002; 99(11):3892-904.
10. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallström E, Khademi M, et al. Variation in interleukin 7 receptor α chain (IL7R) influences risk of multiple sclerosis. Nat Genet 2007; 39(9):1108-13.
11. Zhang Z, Duvefelt K, Svensson F, Masterman T, Jonasdottir G, Salter H, Emahazion T, Hellgren D, Falk G, Olsson T, Hillert J. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun 2005; 6(2):145-52.
12. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, et al. Interleukin 7 receptor α chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 2007; 39(9):1083-91.
13. Weber F, Fontaine B, Cournu-Rebeix I, Kroner A, Knop M, Lutz S, Müller-Sarnowski F, Uhr M, Bettecken T, Kohli M, Ripke S. IL2RA and IL7RA genes
confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun 2008; 9(3):259-63.
14. Fang L, Isobe N, Yoshimura S, Yonekawa T, Matsushita T, Masaki K, Doi H, Ochi K, Miyamoto K, Kawano Y, Kira J. Interleukin-7 receptor alpha gene polymorphism influences multiple sclerosis risk in Asians. Neurology 2011; 76(24):2125-7.
15. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13(3):227-31.
16. Eftekharian MM, Sayad A, Omrani MD, Ghannad MS, Noroozi R, Mazdeh M, et al. Single nucleotide polymorphisms in the FOXP3 gene are associated with increased risk of relapsing-remitting multiple sclerosis. Hum Antibodies 2016; 24(3-4):85-90.
17. Shokrgozar MA, Sarial S, Amirzargar A, Shokri F, Rezaei N, Arjang Z, et al. IL-2, IFN-γ, and IL-12 gene polymorphisms and susceptibility to multiple sclerosis. J Clin Immunol 2009; 29(6):747-51.
18. Nazdik MK, Taheri M, Sajjadi E, Arsang-Jang S, Koohpar ZK, Inoko H, et al. Increased expression ratio of matrix metalloproteinase-9 (MMP9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) RNA levels in Iranian multiple sclerosis patients. Hum Antibodies 2016; 24(3-4):65-70.
19. Hamedani SY, Taheri M, Omrani MD, Sajjadi E, Mazdeh M, Panah AS, Sayad A. Up regulation of MMP9 gene expression in female patients with multiple sclerosis. Human Antibodies 2016; 24(3-4):59-64.
20. Alcina A, Fedetz M, Ndagire D, Fernandez O, Leyva L, Guerrero M, et al. The T244I variant of the interleukin‐7 receptor‐alpha gene and multiple sclerosis. Tissue antigens 2008; 72(2):158-61.
21. Ramagopalan SV, Anderson C, Sadovnick AD, Ebers GC, Matesanz F. Genomewide study of multiple sclerosis. N Engl J Med 2007; 357(21):2199-200.
22. O'Doherty C, Kantarci O, Vandenbroeck K. IL7RA polymorphisms and susceptibility to multiple sclerosis. N Engl J Med 2008; 358(7):753-4.
23. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N engl J med 2007; 357(9):851-62.
24. Akkad DA, Hoffjan S, Petrasch-Parwez E, Beygo J, Gold R, Epplen JT. Variation in the IL7RA and IL2RA genes in German multiple sclerosis patients. J Autoimmun 2009; 32(2):110-5.
25. Kallio SP, Jakkula E, Purcell S, Suvela M, Koivisto K, Tienari PJ, et al. Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS. Hum Mol Genet 2009; 18(9):1670-83.
26. Svejgaard A. The immunogenetics of multiple sclerosis. Immunogenetics 2008; 60(6):275-86.
27. Stanković A, Dinčić E, Ristić S, Lovrečić L, Čizmarević NS, Djurić T, et al. Interleukin 7 receptor alpha polymorphism rs6897932 and susceptibility to multiple sclerosis in the Western Balkans. Mult Scler 2010; 16(5):533-6.
28. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7(4):248-9.
29. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res 2001; 11(5):863-74.
30. Yue P, Melamud E, Moult J. SNPs3D: candidate gene and SNP selection for association studies. BMC bioinformatics 2006; 7(1):166.
31. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic acids res 2012; 40(D1):D930-4.
32. Lundström W, Highfill S, Walsh ST, Beq S, Morse E, Kockum I, et al. Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity. Proc Natl Acad Sci U S A 2013; 110(19):E1761-70.
33. McKay FC, Hoe E, Parnell G, Gatt P, Schibeci SD, Stewart GJ, Booth DR. IL7Rα expression and upregulation by IFNβ in dendritic cell subsets is haplotype-dependent. PloS one 2013; 8(10):e77508.
34. Evsyukova I, Bradrick SS, Gregory SG, Garcia-Blanco MA. Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6. RNA 2013; 19(1):103-15.
35. Sombekke MH, van der Voort LF, Kragt JJ, Nielsen JM, Guzel H, Visser A, Oudejans CB, Crusius JB, Peña AS, Vrenken H, Polman CH. Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis. Mult Scler 2011; 17(8):922-30.
36. Taheri M, Ghafouri-Fard S, Solgi G, Sayad A, Mazdeh M, Omrani MD. Determination of cytokine levels in multiple sclerosis patients and their relevance with patients' response to Cinnovex. Cytokine 2017; 96:138-43.
37. Sayad A, Ghafouri-Fard S, Omrani M D, Noroozi R, Taheri M. Myxovirus resistance protein A (MxA) polymorphism is associated with IFNβ response in Iranian multiple sclerosis patients. Neurological Sciences 2017;1-7.
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| Issue | Vol 16, No 4 (2017) | |
| Section | Original Article(s) | |
| Keywords | ||
| Gene expression IL7Rα gene Multiple sclerosis Polymorphism | ||
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