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Plasma Interleukin-21 Levels and Genetic Variants Are Associated With

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Plasma Interleukin-21 Levels and Genetic Variants Are Associated With Hao et al. BMC Musculoskeletal Disorders (2021) 22:246 https://doi.org/10.1186/s12891-021-04111-0 RESEARCH ARTICLE Open Access Plasma interleukin-21 levels and genetic variants are associated with susceptibility to rheumatoid arthritis Youguo Hao1†, Lijun Xie2†, Jing Xia1, Zhen Liu3,4, Baoxiu Yang5 and Minqin Zhang5* Abstract Background: Rheumatoid Arthritis (RA) is a chronic inflammatory condition characterized by autoantibodies development and an elevated spectrum of pro-inflammatory cytokines. Previous reports highlighted a relationship between IL-21and the pathogenesis of RA. Although elevated IL-21 levels have been reported in RA patients, the association of common IL-21 genetic variants with a predisposition to RA development in the Chinese population lacks. Materials and methods: Five hundred and fourteen Chinese subjects (healthy controls: 303 and rheumatoid arthritis patients: 211) were enrolled in the study. Clinical data of patients were collected from medical records, and patients were treated as per the guidelines. Common single nucleotide polymorphisms in the IL-21 gene (rs907715, rs2221903, rs2055979 and rs6822844) were genotyped by TaqMan SNPs genotyping method. IL-21 level in plasma of RA patients and healthy subjects was measured by ELISA. Results: The plasma level of IL-21 was significantly higher in subjects with rheumatoid arthritis relative to healthy controls (p < 0.0001). A positive correlation was observed between IL-21 level and DAS28 score, indicating the association of the cytokine with the worsening of the disease (Spearman r = 0.61, p < 0.0001). The prevalence of AA genotype (rs2055979) was significantly higher in RA subjects than in the controls (p < 0.0001, χ2 = 34.73, OR = 4.34, 95% CI = 2.623 to 7.219). Furthermore, elevated plasma IL-21 was observed in the rs2055979-AA genotype compared to CC type (p < 0.0001). Conclusion: IL-21 plays a crucial function in rheumatoid arthritis pathogenesis. IL-21 rs2055979 polymorphism is associated with IL-21 plasma levels and is predisposed to RA development in the Chinese population. Keywords: Rheumatoid arthritis, Interleukin-21, Polymorphism, Chinese Introduction the formation of autoantibodies, inflammation, and en- Autoimmune diseases are characterized by the unregu- largement of synovial tissues leading to the destruction lated activation of the immune system, which attacks of bones and cartilages [2]. The involvement of genetic and damages various tissue systems. Although various and environmental factors has been demonstrated with autoimmune disorders are reported worldwide, rheuma- the development of RA [3], and the severity of the dis- toid arthritis (RA) remained the most prevalent one [1]. eases depends on several risk factors. Although the dis- RA is a systemic autoimmune disease distinguished by ease’s etiology is not fully understood, it is presumed that multiple inflammatory molecules such as cytokines * Correspondence: [email protected] and chemokines play an essential role in disease progres- † Youguo Hao and Lijun Xie contributed equally to this work. sion and pathogenesis [4, 5]. Various pro-inflammatory 5Department of Chinese Medicine, Wuhan Fourth Hospital, Puai Hospital, α β Tongji Medical College, Huazhong University of Science and Technology, cytokines such as TNF- , IL-1 , IL-6, and IL-17, have Wuhan, Hubei 430033, China been shown to induce the destruction of cartilages, Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Hao et al. BMC Musculoskeletal Disorders (2021) 22:246 Page 2 of 9 adjacent bone erosions and increase the severity of the In the present study, we performed hospital-based RA pathogenesis [6]. Based on these observations, pro- case-control research to decipher the role of IL-21 in RA inflammatory molecules’ regulation has been a crucial pathogenesis and clinical severity. Furthermore, four targeting approach for developing a possible therapeutic common SNPs were genotyped and explored a possible measure against RA. Mainly, inhibition of these inflam- association between IL-21 polymorphisms and predis- matory mediators using the monoclonal antibody ap- position to RA development in the Chinese population. proach is of interest that primarily aimed at hindering the synovial inflammation [7]. However, there are many Materials and methods side effects of these monoclonal antibody-based therap- Study population ies. Additionally, due to prolonged use, these treatment Two hundred eleven rheumatoid arthritis patients (156 fe- options become ineffective. Therefore, there is always a males and 55 males) were recruited in the present study quest to develop a newer therapeutic approach for the from January 2018 to December 2019. All patients visited treatment of RA, which can be achieved by venturing or admitted in the Department of Rehabilitation, Shanghai into the pathological role of several other inflammatory Putuo People’s Hospital rheumatology division of the hos- molecules. pital and fulfilled the 2010 criteria for American College Interleukin-21 (IL-21) cytokine is a member of the IL- of Rheumatology/European League against Rheumatism 2 family mainly produced by CD4+ T cells and natural criteria for the classification of RA [24]wereenrolledin killer T cells (NKT) [8]. However, several reports have the study. The mean age of patients was 42.9 ± 13.5 years, also highlighted the production of IL-21 by CD8+ T and the duration of diseases was 18.3 ± 9.4 months. The cells, B cells, macrophages, monocytes, and dendritic exclusion criteria included hypo or hyperthyroidism, dia- cells [9]. IL-21 plays a vital role in the regulation of both betes, other autoimmune disorders, chronic liver failure, innate and adaptive immune systems [10]. Notably, IL- acute/chronic diarrhea, and congestive heart failure. Three 21 controls the differentiation of Th17 cells, B cell acti- hundred three healthy controls hailing from similar geo- vation, and immunoglobulins production [11–13]. The graphical areas, with a mean age of 46.1 ± 18.3 years, were role of IL-21 in the pathogenesis of RA is poorly under- included in the study. RA patients’ various clinical data, stood. Elevated levels of IL-21 has been demonstrated in such as numbers of swollen and tender joints, disease the synovial tissue of RA patients [14, 15]. Further, in activity score (DAS 28), and swollen joints count (SJC) the experimental arthritis model, the blockade of IL-21/ were collected from medical records. Further, based on IL-21 receptor pathways significantly improved disease DAS28 scores, patients were sub-grouped into low severity [16], suggesting an essential role of IL-21 in dis- (DAS 28, < 3.2), intermediate (DAS 28, 3.2–5.1), and ease pathogenesis. Increased IL-21 has also been associ- high (DAS 28, > 5.1), as per the classification criteria ated with higher chances of osteoclastogenesis in for disease activity by European League against humans and mice [15]. Rheumatism (EULAR) [25]. Different biochemical pa- In humans, the gene encoding IL-21 is located at the rameters such as C-reactive protein (CRP), rheumatoid long arm of the fourth chromosome (q26–27). IL-21 factor (RF), erythrocytic sedimentation rate (ESR), and gene spans about 8.44 kb of DNA and consists of six antibodies to cyclic citrullinated peptides (anti-CCP exons and five introns. Various single nucleotide poly- antibodies) were also examined. All patients were morphisms (SNPs) have been reported (https://www. treated with disease-modifying anti-rheumatic drugs ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=59067). Asso- (DMARDs) alone or combined with glucocorticoids ciation of different SNPs with autoimmune disorders (GCs). Details of treatments are shown in Table 2.The such as systemic lupus erythematosus [17], graves dis- study was carried out according to the Declaration of ease [18], and inflammatory bowel disease [19, 20] have Helsinki on ethical principles for medical research in- been documented. Various reports have shown a signifi- volving human subjects [26]. The study protocol was cant association of IL-21 polymorphisms and RA in dif- approved by the Institutional Human Ethical Commit- ferent populations such as Netherlanders [21], Algerian tee of Shanghai Putuo People’s Hospital (PTRM [22], Columbian [19]. A recent meta-analysis with nine YY20200826), and written informed consent was ob- studies [23] demonstrated decreased susceptibility of tained from each participant. subjects with IL-21 rs6822844
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