Volume 9, Issue 2 (Vol.9 No.2 Jul 2020)                   rbmb.net 2020, 9(2): 129-139 | Back to browse issues page

XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Asouri M, Alinejad Rokni H, Sahraian M A, Fattahi S, Motamed N, Doosti R, et al . Association of HLA-DRA and IL2RA Polymorphisms with the Severity and Relapses Rate of Multiple Sclerosis in an Iranian Population. rbmb.net. 2020; 9 (2) :129-139
URL: http://rbmb.net/article-1-453-en.html
Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
Abstract:   (381 Views)
Background: Multiple sclerosis (MS) is a multifactorial condition in which many genetic and environmental factors interfere. The association between genes involved in the immune system and MS was previously reported. The aims of this study were to evaluate 14 SNPs of HLA-DRA, 14 SNPs of IL2RA with severity of MS through Expanded Disability Status Scale (EDSS) and Annualized Relapse Rate (ARR).

Methods: 102 patients with MS referred to Sina hospital in Tehran, Iran, were diagnosed and studied based on McDonald’s guideline, clinical signs, and brain imaging procedures. All patients were included in the study following informed consent. Genotyping study of 14 variants in the HLA-DRA, and 14 variants in IL2RA was conducted by Sanger sequencing. Disease outcomes including EDSS and ARR were registered. Outcome measures between different genotypes of each SNPs were compared separately.

Results: Among 14 SNPs in IL 2RA the genotypes of rs12722489 showed a significant association with ARR in two consecutive years. Mean ARR1 was 1.06±1.12, 0.20±0.34 and 0.31±.50 for AA, GA, and GG genotypes, respectively (p value= 0.008). Mean ARR2 was 1.5±1.08, 0.28±0.40, and 0.42±0.55 for AA, GA, and GG, respectively (p value= 0.001). Regression analysis showed a significant association between rs12722489 with ARR1 and ARR2, removing the potential confounding mediators. No significant association was found between SNPs in HLA-DRA with the attack rate and severity of MS.

Conclusions: The rs12722489 of IL-2RA has an association with ARR, but not with EDSS.
Full-Text [PDF 226 kb]   (147 Downloads)    
Type of Article: Original Article | Subject: Molecular Biology
Received: 2020/01/27 | Accepted: 2020/02/2 | Published: 2020/10/7

References
1. Alcina A, Abad-Grau Mdel M, Fedetz M, Izquierdo G, Lucas M, Fernandez O, et al. Multiple sclerosis risk variant HLA-DRB1* 1501 associates with high expression of DRB1 gene in different human populations. PLoS One. 2012;7(1): e29819. [DOI:10.1371/journal.pone.0029819] [PMID] [PMCID]
2. Hauser SL, Oksenberg JR. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron. 2006;52(1):61-76. [DOI:10.1016/j.neuron.2006.09.011] [PMID]
3. Isobe N, Keshavan A, Gourraud P-A, Zhu AH, Datta E, Schlaeger R, et al. Association of HLA genetic risk burden with disease phenotypesin multiple sclerosis. JAMA Neurol. 2016;73(7):795-802. [DOI:10.1001/jamaneurol.2016.0980] [PMID] [PMCID]
4. Hollenbach JA, Oksenberg JR. The immunogenetics of multiple sclerosis: a comprehensive review. J Autoimmun. 2015;64:13-25. [DOI:10.1016/j.jaut.2015.06.010] [PMID] [PMCID]
5. Simpson S, Blizzard L, Otahal P, Van der Mei I, Taylor B. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(10):1132-41. [DOI:10.1136/jnnp.2011.240432] [PMID]
6. Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 2010;9(5):520-32. [DOI:10.1016/S1474-4422(10)70064-8]
7. Hosseinzadeh A, Baneshi MR, Sedighi B, Kermanchi J, Haghdoost AA. Incidence of multiple sclerosis in Iran: a nationwide, population-based study. Public Health. 2019;175:138-144. [DOI:10.1016/j.puhe.2019.07.013] [PMID]
8. Stadelmann C, Wegner C, Brück W. Inflammation, demyelination, and degeneration-recent insights from MS pathology. Biochim Biophy Acta. 2011;1812(2):275-82. [DOI:10.1016/j.bbadis.2010.07.007] [PMID]
9. Ebers G, Sadovnick A, Risch N. A genetic basis for familial aggregation in multiple sclerosis. Canadian Collaborative Study Group. Nature. 1995;377(6545):150-1. [DOI:10.1038/377150a0] [PMID]
10. Ebers GC, Yee IM, Sadovnick A, Duquette P. Conjugal multiple sclerosis: Population‐based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group. Ann Neurol. 2000;48(6):927-31. https://doi.org/10.1002/1531-8249(200012)48:6<927::AID-ANA14>3.0.CO;2-F [DOI:10.1002/1531-8249(200012)48:63.0.CO;2-F]
11. Willer C, Dyment D, Risch N, Sadovnick A, Ebers G, Group CCS. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A. 2003;100(22):12877-82. [DOI:10.1073/pnas.1932604100] [PMID] [PMCID]
12. Bertrams J, Kuwert E, Liedtke U. HL‐A antigens and multiple sclerosis. Tissue Antigens. 1972;2(5):405-8. [DOI:10.1111/j.1399-0039.1972.tb00060.x] [PMID]
13. Naito S, Namerow N, Mickey MR, Terasaki PI. Multiple sclerosis: association with HL-A3. Tissue Antigens. 1972;2(1):1-4. [DOI:10.1111/j.1399-0039.1972.tb00111.x] [PMID]
14. 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. [DOI:10.1056/NEJMoa073493] [PMID]
15. Matesanz F, Caro-Maldonado A, Fedetz M, Milne RL, Guerrero M, Delgado Cn, et al. IL2RA/CD25 polymorphisms contribute to multiple sclerosis susceptibility. J Neurol. 2007;254(5):682-4. [DOI:10.1007/s00415-006-0416-4] [PMID]
16. Alcina A, Fedetz M, Ndagire D, Fernandez O, Leyva L, Guerrero M, et al. IL2RA/CD25 gene polymorphisms: uneven association with multiple sclerosis (MS) and type 1 diabetes (T1D). PLoS One. 2009;4(1):e4137. [DOI:10.1371/journal.pone.0004137] [PMID] [PMCID]
17. Cavanillas ML, Alcina A, Núñez C, De Las Heras V, Fernández-Arquero M, Bartolomé M, et al. Polymorphisms in the IL2, IL2RA and IL2RB genes in multiple sclerosis risk. Eur J Hum Genet. 2010;18(7):794-9. [DOI:10.1038/ejhg.2010.15] [PMID] [PMCID]
18. Maier LM, Lowe CE, Cooper J, Downes K, Anderson DE, Severson C, et al. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production. PLoS Genet. 2009;5(1):e1000322. [DOI:10.1371/journal.pgen.1000322] [PMID] [PMCID]
19. Perera D, Stankovich J, Butzkueven H, Taylor BV, Foote SJ, Kilpatrick TJ, et al. Fine mapping of multiple sclerosis susceptibility genes provides evidence of allelic heterogeneity at the IL2RA locus. J Neuroimmunol. 2009;211(1-2):105-9. [DOI:10.1016/j.jneuroim.2009.03.010] [PMID]
20. Rubio JP, Stankovich J, Field J, Tubridy N, Marriott M, Chapman C, et al. Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians. Genes Immun. 2008;9(7):624-30. [DOI:10.1038/gene.2008.59] [PMID]
21. Barton A, Thomson W, Ke X, Eyre S, Hinks A, Bowes J, et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat Genet. 2008;40(10):1156-9. [DOI:10.1038/ng.218] [PMID] [PMCID]
22. Harley JB, Alarcon-Riquelme ME, Criswell LA, Jacob CO, Kimberly RP, Moser KL, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40(2):204-10. [DOI:10.1038/ng.81] [PMID] [PMCID]
23. Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R, et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet. 2007;39(9):1074-82. [DOI:10.1038/ng2102] [PMID]
24. International Multiple Sclerosis Genetics Consortium (IMSGC). Refining genetic associations in multiple sclerosis. Lancet Neurol. 2008;7(7):567-9. [DOI:10.1016/S1474-4422(08)70122-4]
25. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-52. [DOI:10.1212/WNL.33.11.1444] [PMID]
26. 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(3):259-63. [DOI:10.1038/gene.2008.14] [PMID]
27. Ainiding G, Kawano Y, Sato S, Isobe N, Matsushita T, Yoshimura S, et al. Interleukin 2 receptor α chain gene polymorphisms and risks of multiple sclerosis and neuromyelitis optica in southern Japanese. J Neurol Sci. 2014;337(1-2):147-50. [DOI:10.1016/j.jns.2013.11.037] [PMID]
28. Dai Y, Li J, Zhong X, Wang Y, Qiu W, Lu Z, et al. IL2RA allele increases risk of neuromyelitis Optica in Southern Han Chinese. Can J Neurol Sci. 2013;40(6):832-5. [DOI:10.1017/S0317167100015973] [PMID]
29. Matiello M, Weinshenker BG, Atkinson EJ, Schaefer-Klein J, Kantarci OH. Association of IL2RA p olymorphisms with susceptibility to multiple sclerosis is not explained by missense mutations in IL2RA. Mult Scler J. 2011;17(5):634-6. [DOI:10.1177/1352458510394703] [PMID]
30. Wang X-X, Chen T. Meta-analysis of the association of IL2RA polymorphisms rs2104286 and rs12722489 with multiple sclerosis risk. Immunol Invest. 2018;47(5):431-442. [DOI:10.1080/08820139.2018.1425699] [PMID]
31. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180-90. [DOI:10.1038/nri3156] [PMID]
32. Chistiakov DA, Voronova NV, Chistiakov PA. The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies. Immunol Lett. 2008;118(1):1-5. [DOI:10.1016/j.imlet.2008.03.002] [PMID]
33. Rose JW, Giovannoni G, Wiendl H, Gold R, Havrdova E, Kappos L, et al. Consistent efficacy of daclizumab beta across patient demographic and disease activity subgroups in patients with relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2017;17:32-40. [DOI:10.1016/j.msard.2017.06.006] [PMID]
34. Baecher‐Allan C, Hafler DA. Human regulatory T cells and their role in autoimmune disease. Immunol Rev. 2006;212:203-16. [DOI:10.1111/j.0105-2896.2006.00417.x] [PMID]
35. Bennetts BH, Teutsch SM, Buhler MM, Heard RN, Stewart GJ. HLA-DMB gene and HLA-DRA promoter region polymorphisms in Australian multiple sclerosis patients. Hum Immunol. 1999;60(9):886-93. [DOI:10.1016/S0198-8859(99)00054-3]
36. Morrison BA, Ucisik-Akkaya E, Flores H, Alaez C, Gorodezky C, Dorak MT. Multiple sclerosis risk markers in HLA-DRA, HLA-C, and IFNG genes are associated with sex-specific childhood leukemia risk. Autoimmunity. 2010;43(8):690-7. [DOI:10.3109/08916930903567492] [PMID]

Add your comments about this article : Your username or Email:
CAPTCHA

Send email to the article author


© 2015 All Rights Reserved | Reports of Biochemistry and Molecular Biology

Designed & Developed by : Yektaweb