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IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population
JNS-13181; No of Pages 4 Journal of the Neurological Sciences xxx (2014) xxx–xxx
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IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population Shunxian Wang a, Hong Zhai b,⁎, Yijun Su c, Yinxu Wang a,d a
Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Sichuan, PR China Department of Neurology, Southwest Hospital, Third Military Medical University, Chongqing, PR China Department of Biology, Western Oregon University, Monmouth, OR, USA d Institute of Neurology, North Sichuan Medical College, Sichuan, PR China b c
a r t i c l e
i n f o
Article history: Received 1 February 2014 Received in revised form 15 April 2014 Accepted 2 May 2014 Available online xxxx Keywords: Multiple sclerosis (MS) Association Polymorphism IL-17 SNP PCR-RFLP
a b s t r a c t Interleukin-17 has been shown to be associated with autoimmune disease. The aim of the current study is to investigate the potential association of IL-17 polymorphisms with multiple sclerosis (MS) in Chinese Han patients. Two SNPs, rs763780 of IL-17F gene and rs2275913 of IL-17A gene were genotyped in 622 MS patients and 743 healthy controls by using a polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Allele and genotype frequencies distribution of the two SNPs were examined between patients and controls using the Chi-Square test. All genotypic and allelic frequencies of the tested IL-17 polymorphisms in control cohort were in Hardy–Weinberg equilibrium. A significantly increased frequency of rs763780 TT genotype (corrected p value (Pc) = 0.024, odds ratio = 1.472, 95% CI = 1.133–1.913) and T allele (corrected P (Pc) = 0.018, odds ratio = 1.446, 95% CI = 1.134–1.844) was detected in MS patients compared with controls. The genotypic and allelic frequencies of rs2275913 in IL-17A gene were not different between patients with MS and controls. These results suggest that rs763780 is associated with multiple sclerosis in a Chinese Han population. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is a T-cell-mediated inflammatory disease of the central nervous system (CNS) characterized by demyelination, axon damage, and neurodegeneration [1]. The underlying pathogenesis of MS remains poorly understood, a plausible hypothesis is that the MS is induced by multifactorial interaction with genetic susceptibility, autoimmune response, and environmental elements involvement [2–4]. Previously, much effort has been made to explore the inherited pathogenic factor of MS, and many HLA and non-HLA genes are identified as susceptible genes for MS. Notably, a particular HLA association with MS to date is with the HLA-DRB1*1501 allele, which is found accounting for approximately 50% of MS patients [5,6]. Despite the fact that HLA genes have been identified as the strongest risk contributor of the susceptibility to MS, the non-HLA region is also generally recognized to contribute a modest effect on MS. A recent meta-analysis confirmed that HLA-DR2 and specifically the DRB1*15 Abbreviations: MS, multiple sclerosis; IL-17, interleukin-17; SNP, single nucleotide polymorphism; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; OR, odds ratio; CI, confidence interval. ⁎ Corresponding author at: Department of Neurology, Southwest Hospital, Third Military Medical University, No. 30 Gaotanyanzheng Street, Shapingba Disctrict, Chongqing 400038, PR China. Tel.: +86 13637809962; fax: +86 23 68754000. E-mail address: [email protected] (H. Zhai).
allele in Chinese MS are less significant risk factors compared with that in Western MS populations. Although the Chinese MS patients still carry relatively high frequency of HLA-DR2 gene (22.8%–37.4%) and HLA-DRB1*15 gene (13.6%), but the Chinese population seems to be one of the ethnic groups resistant to conventional MS. Such results may be explained as the effect of non-HLA genes [7]. Numerous association studies have implicated a variety of potential non-HLA contributory loci/genes for MS, such as interleukin-7 receptor (IL-7r), IL-2r, IL-6 and dipeptidyl-peptidase-6 (DPP6) [8–11], although for some of these genes the effects are only with limited significance and are certainly not enough to fully explain the genetic susceptibility for MS. Since MS is principally recognized as an autoimmune disease, the genes that loom large in the immune process might probably be of highly serious pathogenicity to MS, such as interleukins (IL). The interleukin 17 (IL-17) cytokine family includes six ligands (IL17A-F) mainly produced by Th17 cells and plays a fairly important role in the activation of T cells, fibroblasts and peripheral blood mononuclear cells (PBMCs), as well as the maturation of dendritic cells [12,13]. IL-17A and IL-17F genes are located at the same chromosome of 6p12 and have the exactly similar expression profile [14]. IL-17 expression is proven to be elevated in patients with MS and is observed to be involved in prompting the progression of active experimental autoimmune encephalomyelitis (EAE), a rodent model of MS [15]. Such results demonstrate the contribution of IL-17 to the underlying mechanism of MS.
http://dx.doi.org/10.1016/j.jns.2014.05.004 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Wang S, et al, IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.05.004
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S. Wang et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
Recently, regarding the association with the susceptibility to certain autoimmune and inflammatory diseases, two single nucleotide polymorphisms (SNPs), one in the IL-17A gene (rs2275913) and one SNP in the IL-17F gene (rs763780), have been widely investigated. The IL-17A SNP, rs2275913, has been shown to be associated with rheumatoid arthritis, gastric carcinogenesis, asthma and ulcerative colitis [16–19]. Another IL-17 SNP rs763780, a His-to-Arg substitution at amino acid 161 (H161R) in the 3rd exon of the IL17F gene, is reported by Kawaguchi. This variant in IL-17F is a naturally occurring IL-17F antagonist which causes blockade of the ability of IL-17F to induce expression of certain cytokines and chemokines. Furthermore, rs763780 is also shown to be positively associated with anti-aquaporin 4 antibodypositive neuromyelitis optica in the Southern Han Chinese [20]. Given the role of IL-17 and its SNPs in the pathogenesis of certain autoimmune diseases, it is of specific interest to investigate the relationship between IL-17A and IL-17F and MS susceptibility in a large Chinese population.
Table 2 Restriction endonuclease and PCR primers. SNPs
Tm (°C)
Primers
Restriction endonuclease
rs763780
60
HSP92II
rs2275913
60
5′-GGGAATGCAAACAAACACCTGAA-3′ 5′-CCGTTCCCATCCAGCAAGAGA-3′ 5′-GCATAACTCTTCTGGCAGCTGTA-3 5′-TGCCCACGGTCCAGAAATAC-3′
XMNI
results, 10% of the samples were directly sequenced by using Sanger dideoxy DNA sequencing technology (Invitrogen Biotechnology Co., Shanghai, China).
2.4. Statistical analysis 2. Methods and materials 2.1. Ethics statement The study was approved by the Ethics Research Committee of The Affiliated Hospital of North Sichuan Medical College. All the investigated patients and controls gave written informed consent for this study. The tenets of the Declaration of Helsinki were conducted during all procedures of this study. 2.2. Participants The study population consisted of 622 Han Chinese patients with MS (435 women, 187 men) who are born in Western China and 743 originmatched normal controls (507 women, 236 men). The average age of the patients with MS in the study was 40.9 ± 11.6 years. The age and gender distribution of the patients with MS and controls are shown in Table 1. No differences were observed in the distribution of age and gender ratio between MS patients and controls. All the MS patients were diagnosed at the Department of Neurology, The Affiliated Hospital of North Sichuan Medical College or the Southwest Hospital of The Third Military Medical University, Chongqing, P. R. China from June 2009 to April 2012. The diagnosis of MS in all patients was made according to the revised McDonald criteria [21]. Healthy controls were collected from people who accepted regular check up at the physical examinations center of the Affiliated Hospital of North Sichuan Medical College or Southwest Hospital and showed no history of chronic CNS diseases. There was no relation between healthy controls and MS patients. 2.3. DNA extraction and genotyping Collected peripheral blood samples were stored at −20 °C until use. Genomic DNA was extracted from peripheral blood leukocyte using the QIAamp blood kit (Qiagen Inc., Valencia, CA). Amplification of the target DNA in the IL-17A and IL-17F genes was carried out by PCR method with proper primers (Table 2) PCR restriction fragment length polymorphism (PCR-RFLP) method was employed for the genotyping of both SNPs. PCR products were digested within a 10 μl reaction volume with appropriate digesting enzyme overnight and then were visualized on fittingly concentrated agarose gels after being stained with a commercial nucleic acid stain (GoldView; SBS Genetech, Beijing, China). Ambiguous samples were repeated. To double-check the accuracy of PCR-RFLP
The frequency of genotype was calculated by direct counting. Allele and genotype frequencies were compared between patients and controls by a χ2 test (SPSS version 16.0; SPSS Inc., Chicago, IL). The Hardy–Weinberg equilibrium was initially determined. To examine if any of the clinical features were associated with gene polymorphisms, a comparison was made concerning the distribution of allele and genotype frequencies between patients with and without these certain clinical features using χ2 test. The relative risk (estimated as the odds ratios [OR]) and 95% confidence intervals (CI) were calculated. The Bonferroni correction was applied to adjust the result of genotypic data according to the number of comparisons (n = total number of loci or haplotypes). The Pc b 0.05 was considered as significant.
3. Results Genotyping was successfully carried out in all enrolled subjects. The frequencies of genotype and allele of the two SNPs in normal controls did not significantly deviate from the Hardy–Weinberg equilibrium (HWE). The average age of the patients with MS in the study was 40.9 ± 11.6 years. The healthy controls included 743 subjects (236 males and 507 females), with an average age of 41.2 ± 11.3 years. The age and gender distribution of the patients with MS and controls are shown in Table 1. Genotype and allele distributions of analyzed SNPs were summarized in Table 3. The frequency of the two tested SNPs in the current studied subjects was compared with the international HapMap subjects to validate the accuracy of these findings, no differences were found. The results showed that there were significant differences between the MS patients and the controls regarding the distribution of genotype and allele frequencies of rs763780. The frequency of T allele of rs763780 was significantly higher in MS patients than in the controls (corrected P (Pc) = 0.018, odds ratio = 1.446, 95% CI = 1.134–1.844), and the TT genotype frequency was significantly increased in MS patients (corrected P (Pc) = 0.024, odds ratio = 1.472, 95% CI = 1.133– 1.913). No significant differences were found between the multiple sclerosis patients and controls regarding the genotype and allele frequencies of rs2275913 in IL-17A gene. The frequency of the CT genotype of rs763780 tended to be lower in MS patients than in healthy controls (p = 0.009). However, the significance faded when the Bonferroni correction was performed (Pc = 0.054).
Table 1 Clinical characteristics in MS patients and healthy controls.
Controls MS patients
Age (y) (mean ± SD)
Male
Female
EDSS score
Onset Age (y)
41.2 ± 11.3 40.9 ± 11.6
236 (31.8%) 187 (30.1%)
507 (68.2%) 435 (69.9%)
N/A 4.0 ± 1.9
N/A 34.8 ± 8.25
Please cite this article as: Wang S, et al, IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.05.004
S. Wang et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
3
Table 3 Frequencies of alleles and genotypes of IL-17A and IL-17F polymorphisms in MS patients and controls. IL-17 SNP
Genotype/allele
MS (N = 622)
Controls (N = 743)
P/Pc value
OR & 95% CI
rs763780
TT CT CC T C GG AG AA G A
507 (81.51%) 113 (18.17%) 2 (0.32%) 1127 (90.59%) 117 (9.41%) 151 (24.28%) 324 (52.09%) 147 (23.63%) 626 (49.60%) 638 (50.40%)
557 (74.97%) 178 (23.96%) 8 (1.07%) 1292 (86.94%) 194 (13.06%) 186 (25.03%) 386 (51.95%) 171 (23.01%) 758 (51.01%) 728 (48.99%)
0.004/0.024 0.009/n.s 0.103/n.s 0.003/0.018 0.003/0.018 0.747/n.s 0.959/n.s 0.788/n.s 0.463/n.s 0.463/n.s
1.472 (1.133–1.913) 0.705 (0.541–0.918) 0.296 (0.063–1.401) 1.446 (1.134–1.844) 0.691 (0.542–0.882) 0.960 (0.750–1.229) 1.006 (0.812–1.245) 1.035 (0.805–1.332) 0.945 (0.814–1.098) 1.058 (0.910–1.229)
rs2275913
Bold values indicate significance at P b 0.05. Pc: Bonferroni corrected p value. CI: Confidence interval.
4. Discussion In the present study, the association of two SNPs in IL-17A and IL-17F genes with MS in a Chinese Han population was investigated. No significant association was detected between the IL-17A polymorphism rs2275913 and MS susceptibility. But the frequency of TT genotype of IL-17F SNP rs763780 was found to be significantly increased in MS patients. Meanwhile, the frequency of T allele was also found to be related to this disease. Although MS was previously thought to be Th1-cell-driven, it is now recognized that a distinct lineage of effector T cells, Th17 cells, is also deeply involved in the occurrence and development of MS. Reports have been made on the autoimmune-initiated demyelinating effect of Th17 cells in patients with MS. Flow cytometric analyses made by Durelli in patients with MS observed higher expression of IL-17 in circulating leukocytes than that in controls [22]. The study of Kroenke and Reboldi revealed that Th17 cells induce and recruit neutrophils to the central nervous system going after adoptive transfer into immature hosts [23,24]. Their finding was further validated by Tzartos and colleagues by spotting IL-17+ cells exist in afflicted areas of MS lesions [25]. Furthermore, study in a rodent model of MS revealed that Th17 cells could promote EAE development by inducing neutrophils, as well as driving the aggregation of immature monocytes into the circulation system [26]. In the aforementioned studies, IL-17 had exhibited its indispensible role in the emergence and progress of MS. Nevertheless, how IL-17 achieved its pathogenic effect had not yet been fully clarified. Although the functional influence of IL-17 was under debate, the polymorphisms of IL-17 were thought to be a possible contributory factor and had gained much interest among scholars. There were numerous reports that the genetic polymorphisms of IL17 gene were associated with the susceptibility to multifarious inflammatory diseases. The promoter SNP of IL-17A gene, rs2275913, had been shown to be related to IL-17 production and to be involved in the development of certain diseases. Espinoza et al. reported that the PBMCs carrying 197A allele of rs2275913 had a greater activity than the 197A-allelenegative PBMCs did in IL-17-producing capacity [27]. Nordang and colleagues found rs2275913 was associated with rheumatoid arthritis in a Northern European population [16]. Arisawa et al. demonstrated that rs2275913 significantly associated with the susceptibility to ulcerative colitis in Japanese population [18]. Important association between Chinese patients with cervical cancer and rs2275913 found by Quan et al. suggested that IL-17 not only influence the susceptibility in inflammatory diseases, but also might be pivotal in a wide spectrum of disorders such as tumorigenesis [28]. Another SNP of IL-17 gene which had also been widely investigated was rs763780, a missense located in the IL-17F exon3 region. Kawaguchi et al. reported that this variant gave rise to a His-to-Arg substitution at amino position 161 (H161R), generated an inartificial antagonist of wild type IL-17F and influenced the risk of asthma [17]. In different cohorts, rs763780 had been universally studied and exhibited its relevance with a number of disorders
such as rheumatoid arthritis, ulcerative colitis and Crohn's disease [16,18,29]. Among Chinese populations, Shu et al. found that rs763780 was significantly associated with Vogt–Koyanagi–Harada syndrome, a polygenic disorder characterized by granulomatous inflammation, and Chen et al. found that rs763780 was related to an elevated vulnerability to inflammatory bowel disease [30,31]. These results suggested that IL-17 gene might play a critical role in the pathogenesis of inflammation diseases. However, it remains unclear whether genetic polymorphisms in IL-17A and IL-17F genes confer risk to multiple sclerosis development. A candidate gene study was conducted to investigate the relationship between the IL-17 polymorphisms and MS in the Chinese population. In the present study, the results showed that rs763780 in IL-17F gene, but not rs2275913 in IL-17A was associated with the susceptibility to multiple sclerosis. The frequency of TT genotype and T allele in patients with MS were significantly higher than that in healthy controls. This result was principally consistent with that reported in asthma and ulcerative colitis in Japanese cohorts [17,18], suggested that the IL-17F gene might exert its role in a shared way among those inflammatory diseases. Interestingly, this result was also in accordance with those reported in inflammatory bowel disease and Vogt–Koyanagi–Harada syndrome in the Chinese population as well [29,30]. Negative results were also observed in asthma and osteoarthristis patients in the European population and skin diseases in the Japanese population [32–34]. These discrepancies revealed the possibility that even in the same disease, the degree of IL-17-dependence might vary among different racial types. Unexpectedly, no association was found between rs2275913 and the susceptibility to MS. Although the IL-17A rs2275913 polymorphism located in upstream of IL-17A gene, it may be close to or within promoter region, but did not have an impact on the amino acid replacement, and might thus be void in the influence of expression of IL-17A. Lack of association has been also seen in a number of studies [29,34]. These results revealed that there were prominent distinctions in gene susceptibility among various diseases. In general, the result of this present investigation indicated that TT genotype and T allele of rs763780 was significantly associated with the susceptibility to multiple sclerosis in the Chinese population. However, this research may have several limitations. It is worthwhile to point out that how this SNP exerts its role to achieve pathogenesis of MS is still under debate. Besides, only two SNPs of IL-17 gene were chosen for this study, there lies the possibility that other IL-17 gene polymorphisms may be associated with multiple sclerosis, further investigations are needed to clarify this issue. Considering the varied prevalence in different cohorts, the difference in magnetic resonance imaging features between Asians and Caucasians, and the different response to interferon treatment for Chinese MS patients in comparison with their Caucasian counterparts, it is suggested that there may exists heterogeneity in the immunogenetical background for MS patients from different races [35,36]. Further studies among people with different genetic background and with a larger cohort are needed to identify the relationship between IL-17 genes and the susceptibility of multiple sclerosis.
Please cite this article as: Wang S, et al, IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.05.004
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S. Wang et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
Conflict of interest There is no conflict of interest among all authors. Author's contribution Shunxian Wang and Hong Zhai conceived the experimental design and participated in the sample collection. Shunxian Wang carried out the genotyping. Yinxu Wang analyzed the data. Hong zhai and Yijun Su wrote and revised the manuscript. All authors approved the final manuscript. Acknowledgment We would like to thank Xiaoming Wang, Prof of Neurology, Department of Neurology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan for his kind and helpful advice in experimental design and data analysis. References [1] Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med 2000;343:938–52. [2] Lassmann H, Bruck W, Lucchinetti CF, et al. The immunopathology of multiple sclerosis: an overview. Brain Pathol 2007;17(3):210–8. [3] Marrie RA. Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol 2004;3(12):709–18. [4] Poser CM. The multiple sclerosis trait and the development of multiple sclerosis: genetic vulnerability and environmental effect. Clin Neurol Neurosurg 2006;108(3):227–33. [5] Kenealy SJ, Babron M-C, Bradford Y, et al. A second generation genomic screen for multiple sclerosis. Am J Hum Genet 2004;75:1070–8. [6] Dyment DA, Ebers GC, Sadovnick AD, et al. Genetics of multiple sclerosis. Lancet Neurol 2004;3:104–10. [7] Qiu Wei, James Ian, Carroll William M, et al. HLA-DR allele polymorphism and multiple sclerosis in Chinese populations: a meta-analysis. Mult Scler 2011;17:382. [8] Gregory SG, Schmidt S, Seth P, et al. Multiple sclerosis genetics group. Interleukin-7 receptor a chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 2007;39:1083–91. [9] Weber F, Fontaine B, Cournu-Rebeix I, et al. IL2RA and IL7RA genes confer susceptibility to multiple sclerosis in two independent European populations. Genes Immun 2008;9:259–63. [10] Yan J, Liu J, Lin CY, et al. Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis. Int J Mol Sci Oct 22 2012;13(10):13667–79. [11] Brambilla P, Esposito F, Lindstrom E, et al. Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans. Neurosci Lett 2012;21(530 (2)):155–60. [12] Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004;21:467–76. [13] Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133–41. [14] Nakae S, Komiyama Y, Nambu Y, et al. Antigen-specific T cell sensitization is impaired in IL17 deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 2002;17:375–87.
[15] Lock C, Hermans G, Pedotti R, et al. Genemicroarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002;8:500–8. [16] Nordang GB, Viken MK, Hollis-Moffatt JE, et al. Association analysis of the interleukin 17A gene in Caucasian rheumatoid arthritis patients from Norway and New Zealand. Rheumatology (Oxford) 2009;48:367–70. [17] Kawaguchi M, Takahashi D, Hizawa N, et al. IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity. J Allergy Clin Immunol 2006;117:795–801. [18] Arisawa T, Tahara T, Shibata T, et al. The influence of polymorphisms of interleukin17A and interleukin-17F genes on the susceptibility to ulcerative colitis. J Clin Immunol 2008;28:44–9. [19] Shibata T, Tahara T, Hirata I, Arisawa T. Genetic polymorphism of interleukin- 17A and -17F genes in gastric carcinogenesis. Hum Immunol 2009;70:547–51. [20] Wang H, Zhong X, Wang K, et al. Interleukin 17 gene polymorphism is associated with anti-aquaporin 4 antibody-positive neuromyelitis optica in the Southern Han Chinese—a case control study. J Neurol Sci Mar 15 2012;314(1–2):26–8. [21] McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7. [22] Durelli L, Conti L, Clerico M, et al. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol 2009;65:499–509. [23] Kroenke MA, Carlson TJ, Andjelkovic AV, et al. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 2008;205:1535–41. [24] Reboldi A, Coisne C, Baumjohann D, et al. C–C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 2009;10(5):514–23. [25] Tzartos JS, Friese MA, Craner MJ, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol Jan 2008;172(1):146–55. [26] Axtell RC, de Jong BA, Boniface K, et al. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 2010;16:406–12. [27] Espinoza JL, Takami A, Nakata K, et al. A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation. PLoS One 2011;6(10):e26229. http://dx.doi.org/10.1371/ journal.pone.0026229 (Electronic publication ahead of print 2011 Oct 20). [28] Quan Y, Zhou B, Wang Y, et al. Association between IL17 polymorphisms and risk of cervical cancer in Chinese women. Clin Dev Immunol 2012;2012:258293. [29] Seiderer J, Elben I, Diegelmann J, et al. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis 2008;14(4):437–45. [30] Shu Q, Yang P, Hou S, et al. Interleukin-17 gene polymorphism is associated with Vogt–Koyanagi–Harada syndrome but not with Behçet's disease in a Chinese Han population. Hum Immunol 2010;71:988–91. [31] Chen B, Zeng Z, Hou J, Chen M, Gao X, Hu P. Association of interleukin-17F 7488 single nucleotide polymorphism and inflammatory bowel disease in the Chinese population. Scand J Gastroenterol 2009;44:720–6. [32] Ramsey CD, Lazarus R, Camargo Jr CA, Weiss ST, Celedon JC. Polymorphisms in the interleukin 17F gene (IL17F) and asthma. Genes Immun 2005;6:236–41. [33] Shibata S, Saeki H, Tsunemi Y, et al. IL-17F single nucleotide polymorphism is not associated with psoriasis vulgaris or atopic dermatitis in the Japanese population. J Dermatol Sci 2009;53:163–5. [34] Southam L, Heath O, Chapman K, Loughlin J. Association analysis of the interleukin 17 genes IL17A and IL17F as potential osteoarthritis susceptibility loci. Ann Rheum Dis 2006;65:556–7. [35] Lau KK, Wong LK, Li LS, et al. Epidemiological study of multiple sclerosis in Hong Kong Chinese: questionnaire survey. Hong Kong Med J Apr 2002;8(2):77–80. [36] Kira J1, Kanai T, Nishimura Y, et al. Western versus Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders. Ann Neurol Oct 1996;40(4):569–74.
Please cite this article as: Wang S, et al, IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.05.004
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population Shunxian Wang a, Hong Zhai b,⁎, Yijun Su c, Yinxu Wang a,d a
Department of Neurology, Affiliated Hospital of North Sichuan Medical College, Sichuan, PR China Department of Neurology, Southwest Hospital, Third Military Medical University, Chongqing, PR China Department of Biology, Western Oregon University, Monmouth, OR, USA d Institute of Neurology, North Sichuan Medical College, Sichuan, PR China b c
a r t i c l e
i n f o
Article history: Received 1 February 2014 Received in revised form 15 April 2014 Accepted 2 May 2014 Available online xxxx Keywords: Multiple sclerosis (MS) Association Polymorphism IL-17 SNP PCR-RFLP
a b s t r a c t Interleukin-17 has been shown to be associated with autoimmune disease. The aim of the current study is to investigate the potential association of IL-17 polymorphisms with multiple sclerosis (MS) in Chinese Han patients. Two SNPs, rs763780 of IL-17F gene and rs2275913 of IL-17A gene were genotyped in 622 MS patients and 743 healthy controls by using a polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). Allele and genotype frequencies distribution of the two SNPs were examined between patients and controls using the Chi-Square test. All genotypic and allelic frequencies of the tested IL-17 polymorphisms in control cohort were in Hardy–Weinberg equilibrium. A significantly increased frequency of rs763780 TT genotype (corrected p value (Pc) = 0.024, odds ratio = 1.472, 95% CI = 1.133–1.913) and T allele (corrected P (Pc) = 0.018, odds ratio = 1.446, 95% CI = 1.134–1.844) was detected in MS patients compared with controls. The genotypic and allelic frequencies of rs2275913 in IL-17A gene were not different between patients with MS and controls. These results suggest that rs763780 is associated with multiple sclerosis in a Chinese Han population. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Multiple sclerosis (MS) is a T-cell-mediated inflammatory disease of the central nervous system (CNS) characterized by demyelination, axon damage, and neurodegeneration [1]. The underlying pathogenesis of MS remains poorly understood, a plausible hypothesis is that the MS is induced by multifactorial interaction with genetic susceptibility, autoimmune response, and environmental elements involvement [2–4]. Previously, much effort has been made to explore the inherited pathogenic factor of MS, and many HLA and non-HLA genes are identified as susceptible genes for MS. Notably, a particular HLA association with MS to date is with the HLA-DRB1*1501 allele, which is found accounting for approximately 50% of MS patients [5,6]. Despite the fact that HLA genes have been identified as the strongest risk contributor of the susceptibility to MS, the non-HLA region is also generally recognized to contribute a modest effect on MS. A recent meta-analysis confirmed that HLA-DR2 and specifically the DRB1*15 Abbreviations: MS, multiple sclerosis; IL-17, interleukin-17; SNP, single nucleotide polymorphism; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; OR, odds ratio; CI, confidence interval. ⁎ Corresponding author at: Department of Neurology, Southwest Hospital, Third Military Medical University, No. 30 Gaotanyanzheng Street, Shapingba Disctrict, Chongqing 400038, PR China. Tel.: +86 13637809962; fax: +86 23 68754000. E-mail address: [email protected] (H. Zhai).
allele in Chinese MS are less significant risk factors compared with that in Western MS populations. Although the Chinese MS patients still carry relatively high frequency of HLA-DR2 gene (22.8%–37.4%) and HLA-DRB1*15 gene (13.6%), but the Chinese population seems to be one of the ethnic groups resistant to conventional MS. Such results may be explained as the effect of non-HLA genes [7]. Numerous association studies have implicated a variety of potential non-HLA contributory loci/genes for MS, such as interleukin-7 receptor (IL-7r), IL-2r, IL-6 and dipeptidyl-peptidase-6 (DPP6) [8–11], although for some of these genes the effects are only with limited significance and are certainly not enough to fully explain the genetic susceptibility for MS. Since MS is principally recognized as an autoimmune disease, the genes that loom large in the immune process might probably be of highly serious pathogenicity to MS, such as interleukins (IL). The interleukin 17 (IL-17) cytokine family includes six ligands (IL17A-F) mainly produced by Th17 cells and plays a fairly important role in the activation of T cells, fibroblasts and peripheral blood mononuclear cells (PBMCs), as well as the maturation of dendritic cells [12,13]. IL-17A and IL-17F genes are located at the same chromosome of 6p12 and have the exactly similar expression profile [14]. IL-17 expression is proven to be elevated in patients with MS and is observed to be involved in prompting the progression of active experimental autoimmune encephalomyelitis (EAE), a rodent model of MS [15]. Such results demonstrate the contribution of IL-17 to the underlying mechanism of MS.
http://dx.doi.org/10.1016/j.jns.2014.05.004 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Wang S, et al, IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.05.004
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S. Wang et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
Recently, regarding the association with the susceptibility to certain autoimmune and inflammatory diseases, two single nucleotide polymorphisms (SNPs), one in the IL-17A gene (rs2275913) and one SNP in the IL-17F gene (rs763780), have been widely investigated. The IL-17A SNP, rs2275913, has been shown to be associated with rheumatoid arthritis, gastric carcinogenesis, asthma and ulcerative colitis [16–19]. Another IL-17 SNP rs763780, a His-to-Arg substitution at amino acid 161 (H161R) in the 3rd exon of the IL17F gene, is reported by Kawaguchi. This variant in IL-17F is a naturally occurring IL-17F antagonist which causes blockade of the ability of IL-17F to induce expression of certain cytokines and chemokines. Furthermore, rs763780 is also shown to be positively associated with anti-aquaporin 4 antibodypositive neuromyelitis optica in the Southern Han Chinese [20]. Given the role of IL-17 and its SNPs in the pathogenesis of certain autoimmune diseases, it is of specific interest to investigate the relationship between IL-17A and IL-17F and MS susceptibility in a large Chinese population.
Table 2 Restriction endonuclease and PCR primers. SNPs
Tm (°C)
Primers
Restriction endonuclease
rs763780
60
HSP92II
rs2275913
60
5′-GGGAATGCAAACAAACACCTGAA-3′ 5′-CCGTTCCCATCCAGCAAGAGA-3′ 5′-GCATAACTCTTCTGGCAGCTGTA-3 5′-TGCCCACGGTCCAGAAATAC-3′
XMNI
results, 10% of the samples were directly sequenced by using Sanger dideoxy DNA sequencing technology (Invitrogen Biotechnology Co., Shanghai, China).
2.4. Statistical analysis 2. Methods and materials 2.1. Ethics statement The study was approved by the Ethics Research Committee of The Affiliated Hospital of North Sichuan Medical College. All the investigated patients and controls gave written informed consent for this study. The tenets of the Declaration of Helsinki were conducted during all procedures of this study. 2.2. Participants The study population consisted of 622 Han Chinese patients with MS (435 women, 187 men) who are born in Western China and 743 originmatched normal controls (507 women, 236 men). The average age of the patients with MS in the study was 40.9 ± 11.6 years. The age and gender distribution of the patients with MS and controls are shown in Table 1. No differences were observed in the distribution of age and gender ratio between MS patients and controls. All the MS patients were diagnosed at the Department of Neurology, The Affiliated Hospital of North Sichuan Medical College or the Southwest Hospital of The Third Military Medical University, Chongqing, P. R. China from June 2009 to April 2012. The diagnosis of MS in all patients was made according to the revised McDonald criteria [21]. Healthy controls were collected from people who accepted regular check up at the physical examinations center of the Affiliated Hospital of North Sichuan Medical College or Southwest Hospital and showed no history of chronic CNS diseases. There was no relation between healthy controls and MS patients. 2.3. DNA extraction and genotyping Collected peripheral blood samples were stored at −20 °C until use. Genomic DNA was extracted from peripheral blood leukocyte using the QIAamp blood kit (Qiagen Inc., Valencia, CA). Amplification of the target DNA in the IL-17A and IL-17F genes was carried out by PCR method with proper primers (Table 2) PCR restriction fragment length polymorphism (PCR-RFLP) method was employed for the genotyping of both SNPs. PCR products were digested within a 10 μl reaction volume with appropriate digesting enzyme overnight and then were visualized on fittingly concentrated agarose gels after being stained with a commercial nucleic acid stain (GoldView; SBS Genetech, Beijing, China). Ambiguous samples were repeated. To double-check the accuracy of PCR-RFLP
The frequency of genotype was calculated by direct counting. Allele and genotype frequencies were compared between patients and controls by a χ2 test (SPSS version 16.0; SPSS Inc., Chicago, IL). The Hardy–Weinberg equilibrium was initially determined. To examine if any of the clinical features were associated with gene polymorphisms, a comparison was made concerning the distribution of allele and genotype frequencies between patients with and without these certain clinical features using χ2 test. The relative risk (estimated as the odds ratios [OR]) and 95% confidence intervals (CI) were calculated. The Bonferroni correction was applied to adjust the result of genotypic data according to the number of comparisons (n = total number of loci or haplotypes). The Pc b 0.05 was considered as significant.
3. Results Genotyping was successfully carried out in all enrolled subjects. The frequencies of genotype and allele of the two SNPs in normal controls did not significantly deviate from the Hardy–Weinberg equilibrium (HWE). The average age of the patients with MS in the study was 40.9 ± 11.6 years. The healthy controls included 743 subjects (236 males and 507 females), with an average age of 41.2 ± 11.3 years. The age and gender distribution of the patients with MS and controls are shown in Table 1. Genotype and allele distributions of analyzed SNPs were summarized in Table 3. The frequency of the two tested SNPs in the current studied subjects was compared with the international HapMap subjects to validate the accuracy of these findings, no differences were found. The results showed that there were significant differences between the MS patients and the controls regarding the distribution of genotype and allele frequencies of rs763780. The frequency of T allele of rs763780 was significantly higher in MS patients than in the controls (corrected P (Pc) = 0.018, odds ratio = 1.446, 95% CI = 1.134–1.844), and the TT genotype frequency was significantly increased in MS patients (corrected P (Pc) = 0.024, odds ratio = 1.472, 95% CI = 1.133– 1.913). No significant differences were found between the multiple sclerosis patients and controls regarding the genotype and allele frequencies of rs2275913 in IL-17A gene. The frequency of the CT genotype of rs763780 tended to be lower in MS patients than in healthy controls (p = 0.009). However, the significance faded when the Bonferroni correction was performed (Pc = 0.054).
Table 1 Clinical characteristics in MS patients and healthy controls.
Controls MS patients
Age (y) (mean ± SD)
Male
Female
EDSS score
Onset Age (y)
41.2 ± 11.3 40.9 ± 11.6
236 (31.8%) 187 (30.1%)
507 (68.2%) 435 (69.9%)
N/A 4.0 ± 1.9
N/A 34.8 ± 8.25
Please cite this article as: Wang S, et al, IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.05.004
S. Wang et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Table 3 Frequencies of alleles and genotypes of IL-17A and IL-17F polymorphisms in MS patients and controls. IL-17 SNP
Genotype/allele
MS (N = 622)
Controls (N = 743)
P/Pc value
OR & 95% CI
rs763780
TT CT CC T C GG AG AA G A
507 (81.51%) 113 (18.17%) 2 (0.32%) 1127 (90.59%) 117 (9.41%) 151 (24.28%) 324 (52.09%) 147 (23.63%) 626 (49.60%) 638 (50.40%)
557 (74.97%) 178 (23.96%) 8 (1.07%) 1292 (86.94%) 194 (13.06%) 186 (25.03%) 386 (51.95%) 171 (23.01%) 758 (51.01%) 728 (48.99%)
0.004/0.024 0.009/n.s 0.103/n.s 0.003/0.018 0.003/0.018 0.747/n.s 0.959/n.s 0.788/n.s 0.463/n.s 0.463/n.s
1.472 (1.133–1.913) 0.705 (0.541–0.918) 0.296 (0.063–1.401) 1.446 (1.134–1.844) 0.691 (0.542–0.882) 0.960 (0.750–1.229) 1.006 (0.812–1.245) 1.035 (0.805–1.332) 0.945 (0.814–1.098) 1.058 (0.910–1.229)
rs2275913
Bold values indicate significance at P b 0.05. Pc: Bonferroni corrected p value. CI: Confidence interval.
4. Discussion In the present study, the association of two SNPs in IL-17A and IL-17F genes with MS in a Chinese Han population was investigated. No significant association was detected between the IL-17A polymorphism rs2275913 and MS susceptibility. But the frequency of TT genotype of IL-17F SNP rs763780 was found to be significantly increased in MS patients. Meanwhile, the frequency of T allele was also found to be related to this disease. Although MS was previously thought to be Th1-cell-driven, it is now recognized that a distinct lineage of effector T cells, Th17 cells, is also deeply involved in the occurrence and development of MS. Reports have been made on the autoimmune-initiated demyelinating effect of Th17 cells in patients with MS. Flow cytometric analyses made by Durelli in patients with MS observed higher expression of IL-17 in circulating leukocytes than that in controls [22]. The study of Kroenke and Reboldi revealed that Th17 cells induce and recruit neutrophils to the central nervous system going after adoptive transfer into immature hosts [23,24]. Their finding was further validated by Tzartos and colleagues by spotting IL-17+ cells exist in afflicted areas of MS lesions [25]. Furthermore, study in a rodent model of MS revealed that Th17 cells could promote EAE development by inducing neutrophils, as well as driving the aggregation of immature monocytes into the circulation system [26]. In the aforementioned studies, IL-17 had exhibited its indispensible role in the emergence and progress of MS. Nevertheless, how IL-17 achieved its pathogenic effect had not yet been fully clarified. Although the functional influence of IL-17 was under debate, the polymorphisms of IL-17 were thought to be a possible contributory factor and had gained much interest among scholars. There were numerous reports that the genetic polymorphisms of IL17 gene were associated with the susceptibility to multifarious inflammatory diseases. The promoter SNP of IL-17A gene, rs2275913, had been shown to be related to IL-17 production and to be involved in the development of certain diseases. Espinoza et al. reported that the PBMCs carrying 197A allele of rs2275913 had a greater activity than the 197A-allelenegative PBMCs did in IL-17-producing capacity [27]. Nordang and colleagues found rs2275913 was associated with rheumatoid arthritis in a Northern European population [16]. Arisawa et al. demonstrated that rs2275913 significantly associated with the susceptibility to ulcerative colitis in Japanese population [18]. Important association between Chinese patients with cervical cancer and rs2275913 found by Quan et al. suggested that IL-17 not only influence the susceptibility in inflammatory diseases, but also might be pivotal in a wide spectrum of disorders such as tumorigenesis [28]. Another SNP of IL-17 gene which had also been widely investigated was rs763780, a missense located in the IL-17F exon3 region. Kawaguchi et al. reported that this variant gave rise to a His-to-Arg substitution at amino position 161 (H161R), generated an inartificial antagonist of wild type IL-17F and influenced the risk of asthma [17]. In different cohorts, rs763780 had been universally studied and exhibited its relevance with a number of disorders
such as rheumatoid arthritis, ulcerative colitis and Crohn's disease [16,18,29]. Among Chinese populations, Shu et al. found that rs763780 was significantly associated with Vogt–Koyanagi–Harada syndrome, a polygenic disorder characterized by granulomatous inflammation, and Chen et al. found that rs763780 was related to an elevated vulnerability to inflammatory bowel disease [30,31]. These results suggested that IL-17 gene might play a critical role in the pathogenesis of inflammation diseases. However, it remains unclear whether genetic polymorphisms in IL-17A and IL-17F genes confer risk to multiple sclerosis development. A candidate gene study was conducted to investigate the relationship between the IL-17 polymorphisms and MS in the Chinese population. In the present study, the results showed that rs763780 in IL-17F gene, but not rs2275913 in IL-17A was associated with the susceptibility to multiple sclerosis. The frequency of TT genotype and T allele in patients with MS were significantly higher than that in healthy controls. This result was principally consistent with that reported in asthma and ulcerative colitis in Japanese cohorts [17,18], suggested that the IL-17F gene might exert its role in a shared way among those inflammatory diseases. Interestingly, this result was also in accordance with those reported in inflammatory bowel disease and Vogt–Koyanagi–Harada syndrome in the Chinese population as well [29,30]. Negative results were also observed in asthma and osteoarthristis patients in the European population and skin diseases in the Japanese population [32–34]. These discrepancies revealed the possibility that even in the same disease, the degree of IL-17-dependence might vary among different racial types. Unexpectedly, no association was found between rs2275913 and the susceptibility to MS. Although the IL-17A rs2275913 polymorphism located in upstream of IL-17A gene, it may be close to or within promoter region, but did not have an impact on the amino acid replacement, and might thus be void in the influence of expression of IL-17A. Lack of association has been also seen in a number of studies [29,34]. These results revealed that there were prominent distinctions in gene susceptibility among various diseases. In general, the result of this present investigation indicated that TT genotype and T allele of rs763780 was significantly associated with the susceptibility to multiple sclerosis in the Chinese population. However, this research may have several limitations. It is worthwhile to point out that how this SNP exerts its role to achieve pathogenesis of MS is still under debate. Besides, only two SNPs of IL-17 gene were chosen for this study, there lies the possibility that other IL-17 gene polymorphisms may be associated with multiple sclerosis, further investigations are needed to clarify this issue. Considering the varied prevalence in different cohorts, the difference in magnetic resonance imaging features between Asians and Caucasians, and the different response to interferon treatment for Chinese MS patients in comparison with their Caucasian counterparts, it is suggested that there may exists heterogeneity in the immunogenetical background for MS patients from different races [35,36]. Further studies among people with different genetic background and with a larger cohort are needed to identify the relationship between IL-17 genes and the susceptibility of multiple sclerosis.
Please cite this article as: Wang S, et al, IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.05.004
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Conflict of interest There is no conflict of interest among all authors. Author's contribution Shunxian Wang and Hong Zhai conceived the experimental design and participated in the sample collection. Shunxian Wang carried out the genotyping. Yinxu Wang analyzed the data. Hong zhai and Yijun Su wrote and revised the manuscript. All authors approved the final manuscript. Acknowledgment We would like to thank Xiaoming Wang, Prof of Neurology, Department of Neurology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan for his kind and helpful advice in experimental design and data analysis. References [1] Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med 2000;343:938–52. [2] Lassmann H, Bruck W, Lucchinetti CF, et al. The immunopathology of multiple sclerosis: an overview. Brain Pathol 2007;17(3):210–8. [3] Marrie RA. Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol 2004;3(12):709–18. [4] Poser CM. The multiple sclerosis trait and the development of multiple sclerosis: genetic vulnerability and environmental effect. Clin Neurol Neurosurg 2006;108(3):227–33. [5] Kenealy SJ, Babron M-C, Bradford Y, et al. A second generation genomic screen for multiple sclerosis. Am J Hum Genet 2004;75:1070–8. [6] Dyment DA, Ebers GC, Sadovnick AD, et al. Genetics of multiple sclerosis. Lancet Neurol 2004;3:104–10. [7] Qiu Wei, James Ian, Carroll William M, et al. HLA-DR allele polymorphism and multiple sclerosis in Chinese populations: a meta-analysis. Mult Scler 2011;17:382. [8] Gregory SG, Schmidt S, Seth P, et al. Multiple sclerosis genetics group. Interleukin-7 receptor a chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet 2007;39:1083–91. [9] Weber F, Fontaine B, Cournu-Rebeix I, et al. IL2RA and IL7RA genes confer susceptibility to multiple sclerosis in two independent European populations. Genes Immun 2008;9:259–63. [10] Yan J, Liu J, Lin CY, et al. Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis. Int J Mol Sci Oct 22 2012;13(10):13667–79. [11] Brambilla P, Esposito F, Lindstrom E, et al. Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans. Neurosci Lett 2012;21(530 (2)):155–60. [12] Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity 2004;21:467–76. [13] Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133–41. [14] Nakae S, Komiyama Y, Nambu Y, et al. Antigen-specific T cell sensitization is impaired in IL17 deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 2002;17:375–87.
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Please cite this article as: Wang S, et al, IL-17F but not IL-17A gene polymorphism confers risk to multiple sclerosis in a Chinese Han population, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.05.004