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The Association of IL7R rs6897932 with Risk of Multiple Sclerosis in Southern Chinese

Authors Zhao Z, Xue J, Zhuo Z, Zhong W, Liu H

Received 1 June 2022

Accepted for publication 17 August 2022

Published 26 August 2022 Volume 2022:18 Pages 1855—1859

DOI https://doi.org/10.2147/NDT.S376066

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Yuping Ning



Zongbo Zhao,* Jianzhong Xue,* Ziliang Zhuo, Wei Zhong, Hui Liu

Department of Neurology and Institute of Neurology, The Affiliated Changshu Hospital of Xuzhou Medical University, Suchow, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hui Liu, Tel/Fax +860512-52925530, Email [email protected]

Objective: To investigate the association between IL7R rs6897932 and multiple sclerosis (MS) in southern Chinese people.
Methods: In total, 147 MS patients and 530 healthy controls were recruited according to the revised McDonald criteria. The TaqMan method was used for genotyping.
Results: With genetic models, we can observe that the additive model, the dominant model, and the recessive model of IL7R rs6897932 were significantly associated with MS [additive model: p=0.032; dominant model (adjusted): p< 0.001, OR=3.61 (95% CI 2.25– 5.83); recessive model (adjusted): p< 0.001, OR=6.80 (95% CI 3.49– 13.89)].
Conclusion: Our results suggest that IL7R rs6897932 is associated with MS in a southern Chinese population. More and larger MS studies to explore the genetic risk factors of MS are warranted.

Keywords: single-nucleotide polymorphism, multiple sclerosis, IL7R, interleukin

Introduction

Multiple sclerosis (MS) is a progressive autoimmune-mediated demyelinating disorder of the central nervous system.1,2 There are four clinical forms of MS: relapsing-remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), and progressive relapsing MS (PRMS).3 The signs of MS vary from person to person, but mainly include problems with vision, painful spasms, numbness, fatigue, weakness, and cognitive impairment. The prevalence of MS in Asia is much lower than that in Western countries.4

The pathogenesis of MS is still unclear. We can observe a genetic predisposition in patients who have MS.1 With the development of genetics, genome-wide association studies (GWAS) have investigated the susceptible loci of MS. IL7R rs6897932 (polymorphism T244I) was reported to be associated with MS. In exon number 6 of the IL7Rα gene, a single-nucleotide polymorphism (SNP) called rs6897932 induces a non-conservative amino acid transition at location 244, in which isoleucine is shifted to threonine 244 (Ile → Thr) (ATC/ACC). This amino acid shift affects the expression product of IL7Rα, which results in variation in the amounts of the membrane-bound isoform and the soluble form. Such modifications are accompanied by the regulation of the interleukin-7 (IL-7) signaling pathway and a direct association of MS with this SNP.5 Although there have been several studies focusing on the association between IL7R rs6897932 and MS in Asian populations, the association between IL7R rs6897932 and MS in southern Chinese people is still unknown.6 In this research, we performed a case–control study, aiming to determine the association between IL7R rs6897932 and MS in southern Chinese people.

Methods

Study Population

Data on age, gender, age at onset of the disease, and disease duration were obtained. The inclusion criteria were based on the revised McDonald criteria for MS, which was diagnosed individually by two experienced neurologists specializing in MS (WZ and HL).7 Patients with clinically isolated syndrome were not included. Patients were not included if they were reluctant to participate. All MS patients were admitted into the ward of the Department of Neurology of the Affiliated Changshu Hospital of Xuzhou Medical University from January 1st, 2015 to December 31st, 2019. Healthy controls were recruited from the local community and other volunteers matched for age and gender. Information on family history was also obtained. All patients and healthy controls were fully informed and signed consent forms. This study was approved by the ethics committee of the Affiliated Changshu Hospital of Xuzhou Medical University.

DNA Preparation and Genotyping

The 2 mL peripheral blood samples for DNA extraction were collected from MS patients and healthy controls by well-trained nurses. DNA was extracted using the phenol–chloroform–isopropyl alcohol method. We genotyped IL7R rs6897932 with real-time polymer chain reaction using TaqMan assays (assay ID: C__2025977_10; ThermoFisher Scientific, catalog number: 4351379). The TaqMan method is based on quantitative polymer chain reaction. The genotype of each sample was detected automatically using an ABI Prism 7500 sequence detection system (Applied Biosystems).

Statistical Analysis

Statistical analysis was performed with the SAS software package (version 9.4 TS1M2; SAS Institute, Cary, NC). The chi-squared test was used to assess Hardy–Weinberg equilibrium (HWE), genotype, and allele distribution between MS patients and healthy controls. Student’s t-test was used to compare differences in age, age at onset of the disease, and disease duration between MS patients and healthy controls. The additive model is CC vs CT vs TT; the dominant model is (CT + TT) vs CC; the recessive model is TT vs (CC + CT); the overdominant model is (CC + TT) vs CT. Risk analysis was performed by logistic regression. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated. The Cochran–Armitage trend test (CATT) was used to calculate allele dosage. Genetic power was calculated using Power and Sample Size Calculations software (version 3.1.2).

Results

In all, 147 MS patients and 530 healthy controls were enrolled in this study. There were no significant differences in age or gender between MS patients and healthy controls. Ten (6.80%) of the MS patients had a family history of the disease. The average age at onset (mean±SD) was 32.46±8.99 years old, and the disease duration was 2.87±1.91 years. IL7R rs6897932 was in HWE (p=0.936) (Table 1).

Table 1 Demographic Information of Cases and Controls

With regard to the genetic models, we can observe that the additive model, the dominant model, and the recessive model of IL7R rs6897932 were significantly associated with MS [additive model: p=0.032; dominant model (adjusted): p<0.001, OR=3.61 (95% CI 2.25–5.83); recessive model (adjusted): p<0.001, OR=6.80 (95% CI 3.49–13.89)] (Table 2).

Table 2 Association of Models With MS Risk

Discussion

To our knowledge, this is the first study demonstrating the association between IL7R rs6897932 and MS in a southern Chinese population. We found that the additive model, the dominant model, and the recessive model of IL7R rs6897932 were significantly associated with MS.

As a key factor regulating the development of T lymphocytes and homeostasis, IL-7 plays an important role in the pathogenesis of MS. IL-7R, also named CD127, is a pleiotropic receptor for thymic stromal lymphopoietin and IL-7.8 The interaction between IL-7 and IL-7R is vital for T cells, including the development, survival, proliferation, and maintenance of memory T cells.9–11 IL-7 also influences the proliferative capacity and cell metabolism.12,13

IL7R rs6897932 is also associated with other immune-related disorders, such as atopic dermatitis, type 1 diabetes mellitus, and inhalation allergy.14 It has been reported that blocking of IL-7R could ameliorate the disease course of MS.15 The risk allele of IL7R rs6897932, “C” allele, could increase the serum concentrations of sIL7R compared with “T” allele carriers.16 IL7R rs6897932 also plays a vital role in T-cell-associated disorders, such as infection with human immunodeficiency virus.17,18

A meta-analysis focusing on the association between IL7R rs6897932 and the susceptibility to MS reported this association in Europeans rather than Asians.19 In this meta-analysis, there were three studies relating to Asian populations (two in Iran, one in Japan).6,20,21 The populations were different between Iran and Japan. Persian people are considered to be Caucasians. Besides, we cannot simply merge the results from Japan with our results because of different allele frequencies. Further research in Chinese populations is warranted.

There are some limitations in our study. First, the number of MS patients recruited in this study is relatively small. MS is a disorder with a low prevalence in China. Therefore, the power of our study is restricted. Further studies are warranted. Secondly, we detected only this locus owing to a limited budget. More loci related to MS should be detected in southern Chinese patients. Thirdly, we did not test the IL-7 level or the IL-7R level in the serum or the cerebrospinal fluid. As an immunological factor, IL-7 is influenced by the use of steroids and immunosuppressants. Many patients had received treatment before being admitted to our hospital, which may have influenced the levels of IL-7 and IL-7R.

Our results suggest that IL7R rs6897932 is associated with MS in southern Chinese people. More and larger studies exploring the genetic risk factors of MS are warranted.

Highlights

  • The additive model of IL7R rs6897932 was associated with MS.
  • The dominant model of IL7R rs6897932 was associated with MS.
  • The recessive model of IL7R rs6897932 was associated with MS.

Authors’ Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Abbreviations

CATT, Cochran–Armitage trend test; CI, confidence interval; GWAS, genome-wide association study; HWE, Hardy–Weinberg equilibrium; IL, interleukin; MS, multiple sclerosis; OR, odds ratio; PPMS, primary progressive multiple sclerosis; PRMS, progressive relapsing multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SNP, single-nucleotide polymorphism; SPMS, secondary progressive multiple sclerosis.

Consent to Participate

Written informed consent was obtained from the participants.

Consent for Publication

The patients signed informed consent regarding the publication of their data and photographs.

Acknowledgment

We thank all the patients who participated in this study.

Funding

This work was supported by grants from the Project of Key Laboratory of Jiangsu Province [XZSYSKF2020013] and Science and Technology Development Project of Suchow [SKJY2021009]. Funds were used in data collection, data analysis and interpretation, and publication.

Disclosure

All authors have seen and approved the manuscript. The authors declare that they have no conflict of interest.

References

1. Baranzini SE, Oksenberg JR. The genetics of multiple sclerosis: from 0 to 200 in 50 years. Trends Genet. 2017;33:960–970. doi:10.1016/j.tig.2017.09.004

2. Kister I, Bacon TE, Chamot E, et al. Natural history of multiple sclerosis symptoms. Int J MS Care. 2013;15:146–156. doi:10.7224/1537-2073.2012-053

3. Jafarzadeh A, Mahdavi R, Jamali M, et al. Increased concentrations of interleukin-33 in the serum and cerebrospinal fluid of patients with multiple sclerosis. Oman Med J. 2016;31:40–45. doi:10.5001/omj.2016.08

4. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–1517. doi:10.1016/s0140-6736(08)61620-7

5. Gregory SG, Schmidt S, Seth P, et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet. 2007;39:1083–1091. doi:10.1038/ng2103

6. Fang L, Isobe N, Yoshimura S, et al. Interleukin-7 receptor alpha gene polymorphism influences multiple sclerosis risk in Asians. Neurology. 2011;76:2125–2127. doi:10.1212/WNL.0b013e31821f466c

7. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–173. doi:10.1016/s1474-4422(17)30470-2

8. Pathak K. The expanding role of IL-7 and thymic stromal lymphopoietin as therapeutic target for rheumatoid arthritis. Expert Opin Ther Targets. 2014;18:581–594. doi:10.1517/14728222.2014.893295

9. Kelly EA, Koziol-White CJ, Clay KJ, et al. Potential contribution of IL-7 to allergen-induced eosinophilic airway inflammation in asthma. J Immunol. 2009;182:1404–1410. doi:10.4049/jimmunol.182.3.1404

10. McKay FC, Swain LI, Schibeci SD, et al. CD127 immunophenotyping suggests altered CD4+ T cell regulation in primary progressive multiple sclerosis. J Autoimmun. 2008;31:52–58. doi:10.1016/j.jaut.2008.02.003

11. Li L, Masucci MG, Levitsky V. Effect of interleukin-7 on the in vitro development and maturation of monocyte derived human dendritic cells. Scand J Immunol. 2000;51:361–371. doi:10.1046/j.1365-3083.2000.00687.x

12. Zhou J, Jin JO, Du J, Yu Q. Innate immune signaling induces IL-7 production, early inflammatory responses, and Sjögren's-like dacryoadenitis in C57BL/6 mice. Invest Ophthalmol Vis Sci. 2015;56:7831. doi:10.1167/iovs.15-17368

13. Arbelaez CA, Glatigny S, Duhen R, et al. IL-7/IL-7 receptor signaling differentially affects effector CD4 + T cell subsets involved in experimental autoimmune encephalomyelitis. J Immunol. 2015;195:1974–1983. doi:10.4049/jimmunol.1403135

14. Mazzucchelli RI, Riva A, Durum SK. The human IL-7 receptor gene: deletions, polymorphisms and mutations. Semin Immunol. 2012;24:225–230. doi:10.1016/j.smim.2012.02.007

15. Ribeiro AR, Rodrigues PM, Meireles C, Di Santo JP, Alves NL. Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. J Immunol. 2013;191:1200–1209. doi:10.4049/jimmunol.1203042

16. O’Connor AM, Crawley AM, Angel JB. Interleukin-7 enhances memory CD8(+) T-cell recall responses in health but its activity is impaired in human immunodeficiency virus infection. Immunology. 2010;131:525–536. doi:10.1111/j.1365-2567.2010.03325.x

17. Hartling HJ, Thørner LW, Erikstrup C, et al. Polymorphisms in the interleukin-7 receptor α gene and mortality in untreated HIV-infected individuals. Aids. 2013;27:1615–1620. doi:10.1097/QAD.0b013e3283606c2d

18. Hartling HJ, Thørner LW, Erikstrup C, et al. Polymorphism in interleukin-7 receptor α gene is associated with faster CD4+ T-cell recovery after initiation of combination antiretroviral therapy. Aids. 2014;28:1739–1748. doi:10.1097/qad.0000000000000354

19. Wu S, Liu Q, Zhu J-M, et al. Association between the IL7R T244I polymorphism and multiple sclerosis risk: a meta analysis. Neurol Sci. 2016;37:1467–1474. doi:10.1007/s10072-016-2608-8

20. Heidari M, Behmanesh M, Sahraian MA. Variation in SNPs of the IL7Ra gene is associated with multiple sclerosis in the Iranian population. Immunol Invest. 2011;40:279–289. doi:10.3109/08820139.2010.540287

21. Majdinasab N, Hosseini Behbahani M, Galehdari H, Mohaghegh M. Association of interleukin 7 receptor gene polymorphism rs6897932 with multiple sclerosis patients in Khuzestan. Iran J Neurol. 2014;13:168–171.

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