Association of Cytokine Gene Polymorphism with Susceptibility of Ankylosing Spondylitis

Raisa Enayet Badhan¹, *Shaheda Anwar², Ahmed Abu Saleh^2, Shaila Akhtar³, Taskin Jahan⁴, Md. Jahangir Alam⁵

¹ Medical officer (Microbiology), Sheikh Hasina National Institute of Burn and Plastic Surgery, Dhaka, Bangladesh.

² Department of Microbiology and Immunology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.

³ Lecturer, Department of Microbiology, Green Life Medical College, Dhaka, Bangladesh.

⁴ Lecturer (Department of Microbiology), Chattagram International Medical College and Hospital, Chattagram, Bangladesh

⁵ Resident (Department of Ophthalmology), Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.

*Corresponding Author

DOI: https://doi.org/10.51244/IJRSI.2024.1101009

Received: 24 December 2023; Revised: 31 December 2023; Accepted: 04 January 2024; Published: 29 January 2024

ABSTRACT

This article reviews various studies on cytokine polymorphism in ankylosing spondylitis and looks for the associations between the susceptibility to disease. To find the pertinent research, a thorough search of the literature was undertaken. Articles were chosen for this review should be met some criteria: Studies should be case control studies, should described the association between the cytokine gene polymorphism (IL-1R2, IL-12B, IL-10, TNF-α and IL-23R) with the pathogenesis of AS, frequencies of genotypes and alleles in case and control groups could be collected. This article reviewed 20 different studies on Cytokine gene polymorphisms. Nine single-nucleotide polymorphisms (SNPs) of IL-23R (rs11209026, rs1004819, rs10489629, rs11465804, rs1343151, rs11209032, rs1495965, rs7517847, rs2201841) are linked to AS susceptibility out of the seventeen SNPs. Additionally, based on ethnicity revealed a noteworthy association between seven IL-23R SNPs and AS susceptibility in Americans and Europeans, but not in Asian population. Furthermore, susceptibility to AS is also conferred by the IL-10–819 C/T, IL-10-1082A/G, G/G genotype and TNF-α−857 C/T polymorphisms, particularly in Asian populations. IL- 1R2 in rs 2310173 polymorphism found to be associated with AS in European, not in Asian.

Keywords: Single nucleotide polymorphism, Interleukin, Tumour necrosis factor, Ankylosing spondylitis.

INTRODUCTION

The chronic inflammatory condition known as ankylosing spondylitis (AS) is characterized by the destruction of cartilage and bone, peripheral arthritis, and axial skeletal ankylosis [1]. This disease primarily affects individuals between the ages of 20 and 60, and its high occurrence results in a significant socioeconomic burden [2]. While the precise immunopathogenesis of this illness remains unclear, a number of studies have suggested that several susceptibility loci contribute significantly to AS vulnerability. More and more data has been suggested that other genetic loci, such as IL-1R2, IL-12B, IL-10, TNF-α, and IL-23R, may also play a role in the aetiology of AS.

Based on genome-wide association studies, IL-23, an IL-12-related cytokine, is thought to be a possible non-HLA candidate in autoimmune illness (GWAS) [3]. Through its ability to promote Th17 cell differentiation and proliferation, IL-23 may have a role in the development of AS [4]. A number of single-nucleotide polymorphisms (SNPs) of the IL-23R have been substantially linked to AS in a number of recent studies, while other research has shown conflicting findings [5-8]. Regarding IL-12B, this gene is 15 kb long, has eight exons, and is mostly controlled at the post-transcriptional level. It is situated in the non-HLA region of chromosome 5q31–33[9]. The relationship between IL-12B polymorphism and the likelihood of developing autoimmune illnesses has been the subject of numerous studies [10-12], but the findings have generated debate [13]. The IL-10 gene is found on chromosome 1 at 1q31–q32[14]. Several SNPs, including −1082G/A, −819 C/T, and −592C/A, have been identified within this area [15]. According to earlier research, IL-10 levels were considerably greater in AS patients than in healthy controls, suggesting that this cytokine may be crucial in the onset of AS [16]. TNF-α is a further contender, exhibiting multiple polymorphism sites within the promoter, including −308 (G/A), −238 (G/A), and −857 (C/T) [17-19]. While some research have hypothesized that these allelic variations would be functionally meaningful [20,21], other publications have shown no discernible changes in the distribution of alleles [22-23] Furthermore, the substantial association between the development of AS and IL-1R2 rs2310173 was first shown by a recent GWAS in a sizable European people [24]. These findings provide evidence for a potential correlation between the pathophysiology of AS and the cytokine gene polymorphisms, such as IL-1R2, IL-12B, TNF-a308A/G, TNF-a-238 A/G, TNF-a-857 C/T, IL-10–819 C/T, IL-10–592 C/A, IL-23R rs11209026, rs1004819, rs10489629, rs11465804, rs1343151, rs10889677, rs11209032, rs1495965, rs7517847, and rs2201841. The relationship between the gene polymorphisms and the disease susceptibility can be summarized in the review article.

METHODOLOGY

Articles to be reviewed were chosen from PubMed, Elsevier Science Direct, China National Knowledge Infrastructure database, Chinese Biomedical database, and Google Scholar. We have chosen the studies for this review should be met the following criteria: (1) Studies should be case control studies. (2) Studies should described the association between the cytokine gene polymorphism (IL-1R2, IL-12B, IL-10, TNF-α and IL-23R) with the pathogenesis of AS; (3) The frequencies of geno types and alleles in case and control groups could be collected.  Studies included at this review are shown in Table 1.

Table 1: Characteristics of individual studies included in the review article

FINDINGS OF DIFFERENT STUDIES

Chronic inflammation is linked to axial and peripheral skeleton abnormalities in AS, an autoimmune rheumatic illness [14]. There has reportedly been an increase in studies over the past few years that examine the part that genetic predisposition plays in AS [5-8], [25-29]. Some of the findings, meanwhile, were debatable. There could be a number of explanations for the contradicting findings, including true genetic variation, ethnic differences, and small sample sizes. This review is carried out to provide a more concise summary of the relationship between the aforementioned gene polymorphisms and the onset of AS.

Particularly, human monocytes, neutrophils, and B cells express the IL-1R2 gene. IL-1R2 is a member of the IL-1 family, which plays a crucial role in the etiology of numerous inflammatory and autoimmune disorders.

IL-1/ IL-1R

The IL-1R2 polymorphism rs2310173 was not linked to AS in the Asian population according to this review. In contrast, it was found that in patients from Europe, this SNP was strongly linked to AS [30-32]. Another study shows, polymorphisms of IL-1/IL-1Ra cytokines seem to be involved in susceptibility and clinical course of SpA in Tunisian patients [33].

IL-12B

The 15 kb long, eight exon-rich IL-12B gene is found on chromosome 5q31–33, outside of the HLA area. Its expression is primarily controlled post-transcriptionally [34].

Many SNPs in the IL-12B gene have been studied in AS patients, however the findings have generated debate [15, 35].

IL-10

According to earlier research, patients with AS appear to produce considerably more IL-10 from CD8 cells than do healthy controls [16]. Numerous cytokines, including IL-10, have known hereditary predispositions [36, 37].

We thus looked at the IL-10 polymorphisms in AS. Our findings demonstrated a substantial difference in the distribution of IL-10–819 C/T allelic frequencies between the AS patients and the control group. On the other hand, there was no discernible link found between AS and IL-10–592C/A allelic polymorphisms. These results concur with those obtained by Lee et al. and Lv et al. [38, 39]. Braga et al. found association of IL- 10-1082 A/G and G/G genotype with susceptibility to AS in Asian population [40].

TNF- α

In this investigation, we discovered a correlation in allelic contrast between TNF-α−857 C/T and AS in every study participant. Nevertheless, neither the total population nor any subgroups showed any discernible correlation between AS susceptibility and TNF-α−238 polymorphisms. Regarding TNF-α−308, allelic comparisons showed no connection across all participants; however, when Asian and American populations were stratified by ethnicity, an association was seen. This finding contradicted a prior study that demonstrated that allele A at position 308 had a population-wide protective effect against AS [20,25, 41-43].

IL-23R

A number of immune cells, including memory T cells, effector T cells, natural killer cells, dendritic cells, and macrophages, bind to the receptor for the inflammatory cytokine IL-23[4]. Numerous autoimmune disorders have been studied in relation to IL-23R, and susceptibility alleles for the protein have been linked to psoriasis arthritis, Crohn’s disease, and inflammatory bowel disease [5, 8, 28].

Except for rs10889677, our results indicate a strong correlation between the IL-23R polymorphisms and AS susceptibility in the general population. It is commonly recognized that because geographic factors induce population dispersion and, in turn, genetic diversity, allelic frequencies of genes frequently differ significantly among various geographic populations.

Seven SNPs of IL-23R, for instance (rs11209026, rs1004819, rs10489629, rs11465804, rs1343151, rs11209032, rs1495965) have been shown in our study to be strongly associated with AS in both Europeans and Americans; however, there is no significant difference between these IL-23R SNPs in the Asian population [8, 15, 44-46].

IL-17A, IL-17F

Another study showed the association of IL-17 F rs 763780 and IL-17 RA rs48419554 G allele with disease severity and can be a potential biomarker of disease severity [47].

Large-scale studies involving many ethnicities should be taken into consideration in the future to confirm genetic correlations with AS susceptibility.

CONCLUSION

In conclusion, this review indicates that the IL-23R polymorphisms, with the exception of the rs10889677, are associated with AS susceptibility. In the subgroup analysis, significant associations were shown in European and American population, but not in the Asian population. This review also found that IL-10–819 C/T, IL- 10-1082 A/G and G/G genotype and TNF-α−857 C/T polymorphism might be associated with AS risk, especially in the Asian population. With the exception of rs10889677, the results of this review suggest that the IL-23R polymorphisms are linked to AS susceptibility. Significant connections were found in the subgroup analysis for the American and European populations, but not for the Asian population. Additionally, our findings suggested that TNF-α−857 C/T polymorphism and IL-10–819 C/T, IL-10-1082 A/G, G/G polymorphism may be linked to AS risk, particularly in the Asian population.

REFERENCES

1. Brown MA, Wordsworth BP, Reveille JD. Genetics of ankylosing spondylitis. Clin Exp Rheumatol 2002;20(6 Suppl 28): S43–9.
2. Bakland G, Gran JT, Becker-Merok A, et al. Work disability in patients with ankylosing spondylitis in Norway. J Rheumatol 2011; 38:479–84.
3. Brown MA. Non-major-histocompatibility-complex genetics of ankylosing spondylitis. Best Pract Res Clin Rheumatol 2006;20: 611–21.
4. Parham C, Chirica M, Timans J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 2002;168:5699–708.
5. Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007;39: 1329–37.
6. Australo-Anglo-American Spondyloarthritis Consortium (TASC), Reveille JD, Sims AM, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 2010;42: 123–7.
7. Davidson SI, Wu X, Liu Y, et al. Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population. Arthritis Rheum 2009;60: 3263–8.
8. Sung IH, Kim TH, Bang SY, et al. IL-23R polymorphisms in patients with ankylosing spondylitis in Korea. J Rheumatol 2009;36: 1003–5.
9. Jung SH, Yim SH, Hu HJ, et al. Genome-wide copy number variation analysis identifies deletion variants associated with ankylosing spondylitis. Arthritis Rheumatol 2014; 66:2103–12.
10. Huang D, Cancilla MR, Morahan G. Complete primary structure, chromosomal localisation, and definition of polymorphisms of the gene encoding the human interleukin-12 p40 subunit. Genes Immun 2000; 1:515–20.
11. Altinova AE, Engin D, Akbay E, et al. Association of polymorphisms in the IL-18 and IL-12 genes with susceptibility to Type 1 diabetes in Turkish patients. J Endocrinol Invest 2010; 33:451–4.
12. Zhou L, Nazarian AA, Xu J, et al. An inducible enhancer required for Il12b promoter activity in an insulated chromatin environment. Mol Cell Biol 2007; 27:2698–712.
13. Hadžija MP, Korolija M, Jemin N, et al. Polymorphisms in the IL-18 and IL-12B genes and their association with the clinical outcome in Croatian patients with Type 1 diabetes. Gene 2013; 512:477–81.
14. Evans DM, Spencer CC, Pointon JJ, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 2011; 43:761–7.
15. Wong RH, Wei JC, Huang CH, et al. Association of IL-12B genetic polymorphism with the susceptibility and disease severity of ankylosing spondylitis. J Rheumatol 2012;39: 135–40.
16. Rudwaleit M, Siegert S, Yin Z, et al. Low T cell production of TNFalpha and IFNgamma in ankylosing spondylitis: its relation to HLA-B27 and influence of the TNF-308 gene polymorphism. Ann Rheum Dis 2001;60: 36–42.
17. Beretta L, Cappiello F, Barili M, et al. Proximal interleukin-10 gene polymorphisms in Italian patients with systemic sclerosis. Tissue Antigens 2007;69: 305–12.
18. Fraile A, Nieto A, Beraún Y, et al. Tumor necrosis factor gene polymorphisms in ankylosing spondylitis. Tissue Antigens 1998;51(4 Pt 1):386–90.
19. McGarry F, Walker R, Sturrock R, et al. The -308.1 polymorphism in the promoter region of the tumor necrosis factor gene is associated with ankylosing spondylitis independent of HLA-B27. J Rheumatol 1999;26: 1110–6.
20. Chung WT, Choe JY, Jang WC, et al. Polymorphisms of tumor necrosis factor-α promoter region for susceptibility to HLA-B27-positive ankylosing spondylitis in Korean population. Rheumatol Int 2011;31: 1167–75.
21. Shiau MY, Lo MK, Chang CP, et al. Association of tumour necrosis factor alpha promoter polymorphisms with ankylosing spondylitis in Taiwan. Ann Rheum Dis 2007; 66:562–3.
22. Sousa E, Caetano-Lopes J, Pinto P, et al. Ankylosing spondylitis susceptibility and severity–contribution of TNF gene promoter polymorphisms at positions -238 and -308. Ann N Y Acad Sci 2009;1173: 581–8.
23. Vargas-Alarcón G, Casasola-Vargas J, Rodríguez-Pérez JM, et al. Tumor necrosis factor-alpha promoter polymorphisms in Mexican patients with spondyloarthritis. Hum Immunol 2006; 67:826–32.
24. Lu MC, Yang KL, Tung CH, et al. Higher LPS-stimulated TNF-alpha mRNA levels in peripheral blood mononuclear cells from Chinese ankylosing spondylitis patients with -308G/A polymorphism in promoter region of tumor necrosis factor: association with distinct A33/B58/Cw10 haplotypes. Rheumatol Int 2008; 29:189–95.
25. Cai Q, Liu CG, Zhan Z. Gene polymorphism of tumornecrosis factor α -857 and -863 sites in ankylosing spondylitis. Lin Chuang Jun Yi Za Zhi 2009;37: 249–51.
26. Rueda B, Orozco G, Raya E, et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann Rheum Dis 2008;67: 1451–4.
27. Rahman P, Inman RD, Gladman DD, et al. Association of interleukin-23 receptor variants with ankylosing spondylitis. Arthritis Rheum 2008;58: 1020–5.
28. De Vos M. Joint involvement associated with inflammatory bowel disease. Dig Dis 2009; 27:511–5.
29. Karaderi T, Harvey D, Farrar C, et al. Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and metaanalysis of published series. Rheumatology 2009;48: 386–9.
30. Bang SY, Kim TH, Lee B et al. Genetic studies of ankylosing spondylitis in Koreans confirm associations with ERAP1 and 2p15 reported in white patients. J Rheumatol 2011; 38:322–4.
31. Chen C, Zhang X, Wang Y. ANTXR2 and IL-1R2 polymorphisms are not associated with ankylosing spondylitis in Chinese Han population. Rheumatol Int 2012; 32:15–19.
32. Xia Y, Liu YQ, Chen K, et al. Association of IL-1R2 genetic polymorphisms with the susceptibility of ankylosing spondylitis in Northern Chinese Han population. Mod Rheumatol 2015; 25:908–12.
33. Tekaya R, Tekaya AB, Sfar I, Gafsi L, Saidane O, Dhaouadi T, Mahmoud I, Gorgi Y, Abdelmoula L. Interleukin-1 gene polymorphisms in axial spondyloarthritis Tunisian patients Etude des polymorphismes du gène codant pour l’interleukine-1 au cours de la spondyloarthrite axiale. La Tunisie medicale. 2020;98(12):986-91.
34. Warrington JA, Bengtsson U. High-resolution physical mapping of human 5q31-q33 using three methods: radiation hybrid mapping, interphase fluorescence in situ hybridization, and pulsed-field gel electrophoresis. Genomics 1994; 24:395–8.
35. Zhou L, Zhang JY, Liu Y. Novel association between IL12B gene polymorphism and risk of ankylosing spondylitis in Ningxia population. Int J Lab Med 2013; 34:1372–5.
36. Turner DM, Williams DM, Sankaran D, et al. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997; 24:1–8.
37. Braga M, Lara-Armi FF, Neves JS, Rocha-Loures MA, Terron-Monich MD, Bahls-Pinto LD, de Lima Neto QA, Zacarias JM, Sell AM, Visentainer JE. Influence of IL10 (rs1800896) polymorphism and TNF-α, IL-10, IL-17A, and IL-17F serum levels in ankylosing spondylitis. Frontiers in immunology. 2021 Jul 5;12: 653611.
38. . Lee WY, Chang YH, Lo MK, et al. Polymorphisms of cytotoxic T lymphocyte-associated antigen-4 and cytokine genes in Taiwanese patients with ankylosing spondylitis. Tissue Antigens 2010; 75:119–26.
39. Lv C, Wang Y, Wang J, et al. Association of Interleukin-10 gene polymorphisms with ankylosing spondylitis. Clin Invest Med 2011; 34:370.
40. Wilson AG, Symons JA, McDowell TL, et al. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997; 94:3195–9.
41. Tong Q, Zhao DB, Bajracharya P, et al. TNF-α -857 and -1031 polymorphisms predict good therapeutic response to TNF-α blockers in Chinese Han patients with ankylosing spondylitis. Pharmacogenomics 2012;13: 1459–67.
42. Ji Y, Yang X, Yang L, et al. Studies on correlation between single-nucleotide polymorphisms of tumor necrosis factor gene and different stages of ankylosing spondylitis. Cell Biochem Biophys 2013;67:915–22.
43. Manolova I, Ivanova M, Stoilov R, et al. Association of single nucleotide polymorphism at position -308 of the tumor necrosis factor-alpha gene with ankylosing spondylitis and rheumatoid arthritis. Biotechnol Biotechnol Equip 2014;28: 1108–14.
44. Dong H, Li Q, Zhang Y, et al. IL23R gene confers susceptibility to ankylosing spondylitis concomitant with uveitis in a Han Chinese population. PLoS One 2013;8: e67505.
45. Daryabor G, Mahmoudi M, Jamshidi A, et al. Determination of IL-23 receptor gene polymorphism in Iranian patients with ankylosing spondylitis. Eur Cytokine Netw 2014; 25:24–9.
46. Su SS, Wang SL, Lu LJ, et al. Association of interleukin-23 receptor gene single nucleotide polymorphisms with ankylosing spondylitis. Ann Clin Lab Sci 2016; 46:470–3.
47. Wielińska J, Świerkot J, Kolossa K, Bugaj B, Chaszczewska-Markowska M, Jeka S, Bogunia-Kubik K. Polymorphisms within genes coding for IL-17A and F and their receptor as clinical hallmarks in ankylosing spondylitis. Mediators of Inflammation. 2021 Oct 27;2021.