IL-7Ra Association and Genotype-Dependent Severity and Response to IFN-β Therapy in Multiple Sclerosis
Abstract
Multiple sclerosis (MS) is a neurodegenerative disease arising from interactions of both environmental and genetic factors. The SNP rs6897932 is located in IL‐7Ra gene associated with MS susceptibility in some population. In this study, we investigated the possible association of SNP rs6897932 with MS susceptibility in 157 Iranian MS patients and 152 healthy controls. We also studied genotype-dependent severity and response to IFN-β in MS. Unlike some previous studies, our results clearly demonstrate that there are no significant differences in distribution of the SNP rs6897932 in our chosen Iranian MS patients and controls. Furthermore our results show, Interferon beta (IFN-β) therapy over a period of two years demonstrated an IL‐7Ra genotype-dependent therapeutic effect in MS population. Patients carrying TT or TC genotypes gave a better response to IFN-β treatment, whereas patients carrying the homozygous CC genotype were the worst responders to IFN-β treatment. In other words, despite the lack of linkage the therapeutic response to the severity and progression of MS was related to the genotype of SNP rs6897932 presented in our patient. Therefore, in light of our findings reported here, to reach higher certainties, further studies are needed to associate IL-7Ra gene with the pathogenesis of MS.
1. Dilokthornsakul P, Valuck RJ, Nair KV, Corboy JR, Allen RR, Campbell JD. Multiple sclerosis prevalence in the United States commercially insured population. Neurology 2016;86:1014-21.
2. Haj MS, Nikravesh A, Kakhki MP, Rakhshi N. Association study of four polymorphisms in the interleukin-7 receptor alpha gene with multiple sclerosis in Eastern Iran. Iran J Basic Med Sci 2015;18:593-8.
3. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007;61:504-13.
4. Friese MA, Fugger L. Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain 005;128:1747-63.
5. Akkad DA, Lee D-H, Bruch K, Haghikia A, Epplen JT, Hoffjan S, et al. Multiple sclerosis in families: risk factors beyond known genetic polymorphisms. Neurogenetics 2016;17:131-5.
6. Baranzini SE, Nickles D. Genetics of multiple sclerosis: swimming in an ocean of data. Curr Opin Neurol 2012;25:239-45.
7. Patsopoulos NA. Genetics of multiple sclerosis: an overview and new directions. Cold Spring Harbor Perspect Med 2018;8:a028951.
8. Bahreini SA, Jabalameli MR, Saadatnia M, Zahednasab H. The role of non-HLA single nucleotide polymorphisms in multiple sclerosis susceptibility. JNeuroimmunol 2010;229:5-15.
9. Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 2008;9:516.
10. Liu H, Huang J, Dou M, Liu Y, Xiao B, Liu X, et al. Variants in the IL7RA gene confer susceptibility to multiple sclerosis in Caucasians: evidence based on 9734 cases and 10436 controls. Sci Rep 2017;7:1207.
11. Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F, et al. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 2008;18:767-78.
12. Sombekke M, van der Voort L, Kragt J, Nielsen J, Guzel H, Visser A, et al. Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis. Mul Scler J 2011;17:922-30.
13. 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;39:1108.
14. Booth D, Arthur A, Teutsch S, Bye C, Rubio J, Armati P, et al. Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis. JMol Med 2005;83:822-30.
15. 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;39:1083-91.
16. O'doherty C, Kantarci O, Vandenbroeck K. IL7RA polymorphisms and susceptibility to multiple sclerosis. N Engl JMed 2008;358:753-4.
17. Heidari M, Behmanesh M, Sahraian M-A. Variation in SNPs of the IL7Ra gene is associated with multiple sclerosis in the Iranian population. Immunol Invest 2011;40:279-89.
18. Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, et al. The IL-7Rα pathway is quantitatively and functionally altered in CD8 T Cells in multiple sclerosis. J Immunol 2012;188:1874-83.
19. Vandenbroeck K. Cytokine gene polymorphisms and human autoimmune disease in the era of genome-wide association studies. JInterferon Cytokine Res 2012;32:139-51.
20. Weber F, Fontaine B, Cournu-Rebeix I, Kroner A, Knop M, Lutz S, et al. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun 2008;9:259-63.
21. Kalousová M, Levová K, Kuběna AA, Jáchymová M, Franková V, Zima T. Comparison of DNA isolation using salting-out procedure and automated isolation (MagNA system). Prep Biochem Biotechnol 2017;47:703-8.
22. Alsahebfosoul F, Salehi R, Etemadifar M, Hosseini AZ, Kazemi M, Farokhi M, et al. Association between CD127 Gene Polymorphism and Susceptibility to Multiple Sclerosis. SOJ Immunol 2016;4:1-4.
23. Kurtzke JF. Geography in multiple sclerosis. JNeurol 1977;215:1-26.
24. Gharagozli K, Poorsaadat L, Harandi AA, Pakdaman H, Kalanie H. Frequency distribution of the first clinical symptoms in the Iranian population with multiple sclerosis. Iran JNeurol 2012;11:118-20.
25. Broadley S, Sawcer S, D’Alfonso S, Hensiek A, Coraddu F, Gray J, et al. A genome screen for multiple sclerosis in Italian families. Genes Immun 2001;2:205-10.
26. Teutsch SM, Booth DR, Bennetts BH, Heard RN, Stewart GJ. Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-α gene and their associations with multiple sclerosis. Eur JHum Genet 2003;11:509-15.
27. Hafler D, Compston A, Sawcer S. Risk alleles for multiple sclerosis genetics consortium. N Engl J Med 2007;357:851-62.
28. Traboulsee AL, Bernales CQ, Ross JP, Lee JD, Sadovnick AD, Vilariño-Güell C. Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression. Neurogenetics 2014;15:165-9.
29. Hoe E, McKay F, Schibeci S, Heard R, Stewart G, Booth D. Interleukin 7 receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon Beta. J Interf Cytokine Res 2010;30:291-8.
30. McKay FC, Hoe E, Parnell G, Gatt P, Schibeci SD, Stewart GJ, et al. IL7Rα expression and upregulation by IFNβ in dendritic cell subsets is haplotype-dependent. PloS One 2013;8:e77508
2. Haj MS, Nikravesh A, Kakhki MP, Rakhshi N. Association study of four polymorphisms in the interleukin-7 receptor alpha gene with multiple sclerosis in Eastern Iran. Iran J Basic Med Sci 2015;18:593-8.
3. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol 2007;61:504-13.
4. Friese MA, Fugger L. Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain 005;128:1747-63.
5. Akkad DA, Lee D-H, Bruch K, Haghikia A, Epplen JT, Hoffjan S, et al. Multiple sclerosis in families: risk factors beyond known genetic polymorphisms. Neurogenetics 2016;17:131-5.
6. Baranzini SE, Nickles D. Genetics of multiple sclerosis: swimming in an ocean of data. Curr Opin Neurol 2012;25:239-45.
7. Patsopoulos NA. Genetics of multiple sclerosis: an overview and new directions. Cold Spring Harbor Perspect Med 2018;8:a028951.
8. Bahreini SA, Jabalameli MR, Saadatnia M, Zahednasab H. The role of non-HLA single nucleotide polymorphisms in multiple sclerosis susceptibility. JNeuroimmunol 2010;229:5-15.
9. Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 2008;9:516.
10. Liu H, Huang J, Dou M, Liu Y, Xiao B, Liu X, et al. Variants in the IL7RA gene confer susceptibility to multiple sclerosis in Caucasians: evidence based on 9734 cases and 10436 controls. Sci Rep 2017;7:1207.
11. Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F, et al. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 2008;18:767-78.
12. Sombekke M, van der Voort L, Kragt J, Nielsen J, Guzel H, Visser A, et al. Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis. Mul Scler J 2011;17:922-30.
13. 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;39:1108.
14. Booth D, Arthur A, Teutsch S, Bye C, Rubio J, Armati P, et al. Gene expression and genotyping studies implicate the interleukin 7 receptor in the pathogenesis of primary progressive multiple sclerosis. JMol Med 2005;83:822-30.
15. 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;39:1083-91.
16. O'doherty C, Kantarci O, Vandenbroeck K. IL7RA polymorphisms and susceptibility to multiple sclerosis. N Engl JMed 2008;358:753-4.
17. Heidari M, Behmanesh M, Sahraian M-A. Variation in SNPs of the IL7Ra gene is associated with multiple sclerosis in the Iranian population. Immunol Invest 2011;40:279-89.
18. Kreft KL, Verbraak E, Wierenga-Wolf AF, van Meurs M, Oostra BA, Laman JD, et al. The IL-7Rα pathway is quantitatively and functionally altered in CD8 T Cells in multiple sclerosis. J Immunol 2012;188:1874-83.
19. Vandenbroeck K. Cytokine gene polymorphisms and human autoimmune disease in the era of genome-wide association studies. JInterferon Cytokine Res 2012;32:139-51.
20. Weber F, Fontaine B, Cournu-Rebeix I, Kroner A, Knop M, Lutz S, et al. IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations. Genes Immun 2008;9:259-63.
21. Kalousová M, Levová K, Kuběna AA, Jáchymová M, Franková V, Zima T. Comparison of DNA isolation using salting-out procedure and automated isolation (MagNA system). Prep Biochem Biotechnol 2017;47:703-8.
22. Alsahebfosoul F, Salehi R, Etemadifar M, Hosseini AZ, Kazemi M, Farokhi M, et al. Association between CD127 Gene Polymorphism and Susceptibility to Multiple Sclerosis. SOJ Immunol 2016;4:1-4.
23. Kurtzke JF. Geography in multiple sclerosis. JNeurol 1977;215:1-26.
24. Gharagozli K, Poorsaadat L, Harandi AA, Pakdaman H, Kalanie H. Frequency distribution of the first clinical symptoms in the Iranian population with multiple sclerosis. Iran JNeurol 2012;11:118-20.
25. Broadley S, Sawcer S, D’Alfonso S, Hensiek A, Coraddu F, Gray J, et al. A genome screen for multiple sclerosis in Italian families. Genes Immun 2001;2:205-10.
26. Teutsch SM, Booth DR, Bennetts BH, Heard RN, Stewart GJ. Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-α gene and their associations with multiple sclerosis. Eur JHum Genet 2003;11:509-15.
27. Hafler D, Compston A, Sawcer S. Risk alleles for multiple sclerosis genetics consortium. N Engl J Med 2007;357:851-62.
28. Traboulsee AL, Bernales CQ, Ross JP, Lee JD, Sadovnick AD, Vilariño-Güell C. Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression. Neurogenetics 2014;15:165-9.
29. Hoe E, McKay F, Schibeci S, Heard R, Stewart G, Booth D. Interleukin 7 receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon Beta. J Interf Cytokine Res 2010;30:291-8.
30. McKay FC, Hoe E, Parnell G, Gatt P, Schibeci SD, Stewart GJ, et al. IL7Rα expression and upregulation by IFNβ in dendritic cell subsets is haplotype-dependent. PloS One 2013;8:e77508
| Files | ||
| Issue | Vol 57, No 4 (2019) | |
| Section | Articles | |
| DOI | https://doi.org/10.18502/acta.v57i4.1839 | |
| Keywords | ||
| Multiple sclerosis IL-7Ra rs689793 | ||
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Hosseinzadeh M, Aminoshareah P, Mohammadi M, Tavasoli AR, Zamani M. IL-7Ra Association and Genotype-Dependent Severity and Response to IFN-β Therapy in Multiple Sclerosis. Acta Med Iran. 2019;57(4):208-215.
