Importance of STAT3 Polymorphisms on the Risk and Clinical Characteristics of Rheumatoid Arthritis
-
Amirhossein Salehi
,
Ebrahim Hazrati
,
Hamta Ranjbar
,
Javad Behroozi
,
Bahram Pakzad
,
Maryam Mousavi
,
Mojtaba Mousavi
,
Marzieh Hossein Balam
,
Mansour Salesi
Abstract
Signal transducer and activator of transcription 3 (STAT3) has been introduced as one of the critical genetic factors in the pathogenesis of rheumatoid arthritis (RA). Single nucleotide polymorphisms (SNPs) in microRNA binding sites, known as miRSNPs, are a class of common variants in the 3′ untranslated regions of genes targeted by miRNAs. miRSNPs unbalance gene expression by disrupting the binding regions of microRNAs. In this study, we intended to evaluate the association of two miRSNPs with the risk of RA development and its clinical features.
We studied 120 Iranian patients with RA and 125 non-RA subjects as controls. The genotypes and alleles of rs1053005 and rs1053023 in each individual were assessed by the high-resolution melting method.
The distribution of STAT3 variants did not differ markedly in RA patients compared to healthy controls. Stratification analysis revealed that rs1053005 was linked with a higher concentration of C-reactive protein and an increased erythrocyte sedimentation rate, two indicators of inflammation and disease activity in RA patients. The rs1053023 variant was correlated with higher levels of creatinine as an indicator of renal involvement.
Our data demonstrate an association between STAT3 variants and clinical characteristics of RA, such as disease activity and probably kidney impairment. However, we did not observe a significant relationship between the two targeted variants and a predisposition to RA.
1. Deenick EK, Pelham SJ, Kane A, Ma CS. Signal Transducer and Activator of Transcription 3 Control of Human T and B Cell Responses. Front Immunol. 2018;9:168.
2. Mathur AN, Chang H-C, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. The Journal of Immunology. 2007;178(8):4901-7.
3. Zhao M, Tan Y, Peng Q, Huang C, Guo Y, Liang G, et al. IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation. Nature communications. 2018;9(1):1-14.
4. Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007;40(1):1-8.
5. Chen SY, Liu MF, Kuo PY, Wang CR. Upregulated expression of STAT3/IL-17 in patients with systemic lupus erythematosus. Clin Rheumatol. 2019;38(5):1361-6.
6. Zhang W, Chen X, Shi S, Wei R, Wang J, Yamanaka N, et al. Expression and activation of STAT3 in chronic proliferative immune complex glomerulonephritis and the effect of fosinopril. Nephrology Dialysis Transplantation. 2005;20(5):892-901.
7. Pace J, Paladugu P, Das B, He JC, Mallipattu SK. Targeting STAT3 signaling in kidney disease. Am J Physiol Renal Physiol. 2019;316(6):F1151-f61.
8. Perniola S, Cacciapaglia F, Natuzzi D, Bizzoca R, Lacarpia N, Iannone F. AB0134 Phosphorelated stat3 expression in peripheral blood mononuclear cells in rheumatoid arthritis. BMJ Publishing Group Ltd; 2018.
9. Isomäki P, Junttila I, Vidqvist K-L, Korpela M, Silvennoinen O. The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels. Rheumatology. 2014;54(6):1103-13.
10. Saito S, Suzuki K, Yoshimoto K, Kaneko Y, Matsumoto Y, Yamaoka K, et al. A new bioassay for measuring the strength of IL-6/STAT3 signal inhibition by tocilizumab in patients with rheumatoid arthritis. Arthritis Research & Therapy. 2017;19(1):231.
11. Deng J, Fan C, Gao X, Zeng Q, Guo R, Wei Y, et al. Signal transducer and activator of transcription 3 hyperactivation associates with follicular helper T cell differentiation and disease activity in rheumatoid arthritis. Frontiers in immunology. 2018;9:1226.
12. Deng Z, Zhao Y, Chen S, Zhao J. Progress in Stat3 and SirT1 gene in the pathogenesis of rheumatoid arthristis. Journal of Medical Postgraduates. 2015:1001-3.
13. Krause A, Scaletta N, Ji J-D, Ivashkiv LB. Rheumatoid arthritis synoviocyte survival is dependent on Stat3. The Journal of Immunology. 2002;169(11):6610-6.
14. Lao M, Shi M, Zou Y, Huang M, Ye Y, Qiu Q, et al. Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis. J Immunol. 2016;196(2):596-606.
15. Oike T, Sato Y, Kobayashi T, Miyamoto K, Nakamura S, Kaneko Y, et al. Stat3 as a potential therapeutic target for rheumatoid arthritis. Scientific Reports. 2017;7(1):10965.
16. Li X, Xie Y, Kang A, Wang Y. New bitongling (NBTL) ameliorates rheumatoid arthritis in rats through inhibiting JAK2/STAT3 signaling pathway. Eur J Histochem. 2021;65(1).
17. Kaneko Y, Ozawa S-i, Sato Y, Kobayashi T, Matsumoto T, Miyamoto K, et al. The Stat3 inhibitor F0648-0027 is a potential therapeutic against rheumatoid arthritis. 2022.
18. Haghikia A, Hoch M, Stapel B, Hilfiker-Kleiner D. STAT3 regulation of and by microRNAs in development and disease. Jak-Stat. 2012;1(3):143-50.
19. He Z, Jiang J, Kokkinaki M, Tang L, Zeng W, Gallicano I, et al. MiRNA-20 and mirna-106a regulate spermatogonial stem cell renewal at the post-transcriptional level via targeting STAT3 and Ccnd1. Stem cells. 2013;31(10):2205-17.
20. Hassani M, Dehani M, Rafie MZ, Esmaeilzadeh E, Davar S, Pakzad B, et al. Investigation of rs531564 polymorphism in the primary microRNA-124 gene in patients with systemic lupus erythematosus and rheumatoid arthritis: association with disease susceptibility and clinical characteristics. Iranian Journal of Allergy, Asthma and Immunology. 2021;20(3):303.
21. Ehtesham N, Zare Rafie M, Esmaeilzadeh E, Dehani M, Davar S, Mosallaei M, et al. Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus. Lupus. 2021;30(8):1273-82.
22. Moszyńska A, Gebert M, Collawn JF, Bartoszewski R. SNPs in microRNA target sites and their potential role in human disease. Open biology. 2017;7(4):170019.
23. Karimzadeh MR, Zarin M, Ehtesham N, Khosravi S, Soosanabadi M, Mosallaei M, et al. MicroRNA binding site polymorphism in inflammatory genes associated with colorectal cancer: literature review and bioinformatics analysis. Cancer gene therapy. 2020;27(10):739-53.
24. Zeinalzadeh S, Kheradmand N, Rasouli G, Esmaeilzadeh E, Pakzad B, Behroozi J, et al. Association of a miRNA-binding site polymorphism in IL-16 gene with disease risk and clinical characteristics of rheumatoid arthritis and systemic lupus erythematosus. Clinical Rheumatology. 2022:1-8.
25. Salehi A, Nasrollahzadeh Sabet M, Esmaeilzadeh E, Mousavi M, Karimi J, Pakzad B. Impact of miRNA-binding site polymorphisms in STAT3 gene on occurrence and clinical characteristics of systemic lupus erythematosus. Lupus. 2022;31(3):338-46.
26. England BR, Tiong BK, Bergman MJ, Curtis JR, Kazi S, Mikuls TR, et al. 2019 update of the American College of Rheumatology recommended rheumatoid arthritis disease activity measures. Arthritis care & research. 2019;71(12):1540-55.
27. Ding C, Chen X, Dascani P, Hu X, Bolli R, Zhang HG, et al. STAT3 Signaling in B Cells Is Critical for Germinal Center Maintenance and Contributes to the Pathogenesis of Murine Models of Lupus. J Immunol. 2016;196(11):4477-86.
28. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nature genetics. 2014;46(8):812-4.
29. Mitsuyama K, Matsumoto S, Masuda J, Yamasaki H, Kuwaki K, Takedatsu H, et al. Therapeutic strategies for targeting the IL-6/STAT3 cytokine signaling pathway in inflammatory bowel disease. Anticancer Research. 2007;27(6A):3749-56.
30. Miyoshi K, Takaishi M, Nakajima K, Ikeda M, Kanda T, Tarutani M, et al. Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor. Journal of Investigative Dermatology. 2011;131(1):108-17.
31. Park JS, Kwok SK, Lim MA, Kim EK, Ryu JG, Kim SM, et al. STA‐21, a promising STAT‐3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis & rheumatology. 2014;66(4):918-29.
32. Edwards LJ, Mizui M, Kyttaris V. Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice. Clinical immunology. 2015;158(2):221-30.
33. Wang R, Cai J, Chen K, Zhu M, Li Z, Liu H, et al. STAT3-NAV2 axis as a new therapeutic target for rheumatoid arthritis via activating SSH1L/Cofilin-1 signaling pathway. Signal Transduction and Targeted Therapy. 2022;7(1):209.
34. Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, et al. Interleukin‐6 and soluble interleukin‐6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast‐like cell formation. Journal of Bone and Mineral Research. 1996;11(1):88-95.
35. Goropevšek A, Holcar M, Pahor A, Avčin T. STAT signaling as a marker of SLE disease severity and implications for clinical therapy. Autoimmunity Reviews. 2019;18(2):144-54.
36. Haas U, Sczakiel G, Laufer S. MicroRNA-mediated regulation of gene expression is affected by disease-associated SNPs within the 3′-UTR via altered RNA structure. RNA Biology. 2012;9(6):924-37.
37. Zandi M, Moghaddam VA, Salehi Z, Mashayekhi F, Dalili S. The Impact of STAT3 rs1053005 Variation on Type 1 Diabetes Mellitus Susceptibility: Association Study and in Silico Analysis. Immunological Investigations. 2022:1-12.
38. Davidson SI, Liu Y, Danoy PA, Wu X, Thomas GP, Jiang L, et al. Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese. Annals of the rheumatic diseases. 2011;70(2):289-92.
39. Stypińska B, Olesińska M, Pawlik A, Paradowska-Gorycka A. Lack of significant association between selected STAT3 polymorphisms and rheumatoid arthritis in the Polish population. Reumatologia/Rheumatology. 2018;56(2):73-9.
40. Kotulska A, Kopeć-Mędrek M, Grosicka A, Kubicka M, Kucharz EJ. Correlation between erythrocyte sedimentation rate and C-reactive protein level in patients with rheumatic diseases. Reumatologia. 2015;53(5):243-6.
41. Kay J, Morgacheva O, Messing SP, Kremer JM, Greenberg JD, Reed GW, et al. Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year. Arthritis Research & Therapy. 2014;16(1):R40.
42. Cylwik B, Chrostek L, Gindzienska-Sieskiewicz E, Sierakowski S, Szmitkowski M. Relationship between serum acute-phase proteins and high disease activity in patients with rheumatoid arthritis. Advances in medical sciences. 2010;55(1):80-5.
43. Yoshida N, He F, Kyttaris VC. T cell–specific STAT3 deficiency abrogates lupus nephritis. Lupus. 2019;28(12):1468-72.
2. Mathur AN, Chang H-C, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. The Journal of Immunology. 2007;178(8):4901-7.
3. Zhao M, Tan Y, Peng Q, Huang C, Guo Y, Liang G, et al. IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation. Nature communications. 2018;9(1):1-14.
4. Harada T, Kyttaris V, Li Y, Juang YT, Wang Y, Tsokos GC. Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007;40(1):1-8.
5. Chen SY, Liu MF, Kuo PY, Wang CR. Upregulated expression of STAT3/IL-17 in patients with systemic lupus erythematosus. Clin Rheumatol. 2019;38(5):1361-6.
6. Zhang W, Chen X, Shi S, Wei R, Wang J, Yamanaka N, et al. Expression and activation of STAT3 in chronic proliferative immune complex glomerulonephritis and the effect of fosinopril. Nephrology Dialysis Transplantation. 2005;20(5):892-901.
7. Pace J, Paladugu P, Das B, He JC, Mallipattu SK. Targeting STAT3 signaling in kidney disease. Am J Physiol Renal Physiol. 2019;316(6):F1151-f61.
8. Perniola S, Cacciapaglia F, Natuzzi D, Bizzoca R, Lacarpia N, Iannone F. AB0134 Phosphorelated stat3 expression in peripheral blood mononuclear cells in rheumatoid arthritis. BMJ Publishing Group Ltd; 2018.
9. Isomäki P, Junttila I, Vidqvist K-L, Korpela M, Silvennoinen O. The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels. Rheumatology. 2014;54(6):1103-13.
10. Saito S, Suzuki K, Yoshimoto K, Kaneko Y, Matsumoto Y, Yamaoka K, et al. A new bioassay for measuring the strength of IL-6/STAT3 signal inhibition by tocilizumab in patients with rheumatoid arthritis. Arthritis Research & Therapy. 2017;19(1):231.
11. Deng J, Fan C, Gao X, Zeng Q, Guo R, Wei Y, et al. Signal transducer and activator of transcription 3 hyperactivation associates with follicular helper T cell differentiation and disease activity in rheumatoid arthritis. Frontiers in immunology. 2018;9:1226.
12. Deng Z, Zhao Y, Chen S, Zhao J. Progress in Stat3 and SirT1 gene in the pathogenesis of rheumatoid arthristis. Journal of Medical Postgraduates. 2015:1001-3.
13. Krause A, Scaletta N, Ji J-D, Ivashkiv LB. Rheumatoid arthritis synoviocyte survival is dependent on Stat3. The Journal of Immunology. 2002;169(11):6610-6.
14. Lao M, Shi M, Zou Y, Huang M, Ye Y, Qiu Q, et al. Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis. J Immunol. 2016;196(2):596-606.
15. Oike T, Sato Y, Kobayashi T, Miyamoto K, Nakamura S, Kaneko Y, et al. Stat3 as a potential therapeutic target for rheumatoid arthritis. Scientific Reports. 2017;7(1):10965.
16. Li X, Xie Y, Kang A, Wang Y. New bitongling (NBTL) ameliorates rheumatoid arthritis in rats through inhibiting JAK2/STAT3 signaling pathway. Eur J Histochem. 2021;65(1).
17. Kaneko Y, Ozawa S-i, Sato Y, Kobayashi T, Matsumoto T, Miyamoto K, et al. The Stat3 inhibitor F0648-0027 is a potential therapeutic against rheumatoid arthritis. 2022.
18. Haghikia A, Hoch M, Stapel B, Hilfiker-Kleiner D. STAT3 regulation of and by microRNAs in development and disease. Jak-Stat. 2012;1(3):143-50.
19. He Z, Jiang J, Kokkinaki M, Tang L, Zeng W, Gallicano I, et al. MiRNA-20 and mirna-106a regulate spermatogonial stem cell renewal at the post-transcriptional level via targeting STAT3 and Ccnd1. Stem cells. 2013;31(10):2205-17.
20. Hassani M, Dehani M, Rafie MZ, Esmaeilzadeh E, Davar S, Pakzad B, et al. Investigation of rs531564 polymorphism in the primary microRNA-124 gene in patients with systemic lupus erythematosus and rheumatoid arthritis: association with disease susceptibility and clinical characteristics. Iranian Journal of Allergy, Asthma and Immunology. 2021;20(3):303.
21. Ehtesham N, Zare Rafie M, Esmaeilzadeh E, Dehani M, Davar S, Mosallaei M, et al. Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus. Lupus. 2021;30(8):1273-82.
22. Moszyńska A, Gebert M, Collawn JF, Bartoszewski R. SNPs in microRNA target sites and their potential role in human disease. Open biology. 2017;7(4):170019.
23. Karimzadeh MR, Zarin M, Ehtesham N, Khosravi S, Soosanabadi M, Mosallaei M, et al. MicroRNA binding site polymorphism in inflammatory genes associated with colorectal cancer: literature review and bioinformatics analysis. Cancer gene therapy. 2020;27(10):739-53.
24. Zeinalzadeh S, Kheradmand N, Rasouli G, Esmaeilzadeh E, Pakzad B, Behroozi J, et al. Association of a miRNA-binding site polymorphism in IL-16 gene with disease risk and clinical characteristics of rheumatoid arthritis and systemic lupus erythematosus. Clinical Rheumatology. 2022:1-8.
25. Salehi A, Nasrollahzadeh Sabet M, Esmaeilzadeh E, Mousavi M, Karimi J, Pakzad B. Impact of miRNA-binding site polymorphisms in STAT3 gene on occurrence and clinical characteristics of systemic lupus erythematosus. Lupus. 2022;31(3):338-46.
26. England BR, Tiong BK, Bergman MJ, Curtis JR, Kazi S, Mikuls TR, et al. 2019 update of the American College of Rheumatology recommended rheumatoid arthritis disease activity measures. Arthritis care & research. 2019;71(12):1540-55.
27. Ding C, Chen X, Dascani P, Hu X, Bolli R, Zhang HG, et al. STAT3 Signaling in B Cells Is Critical for Germinal Center Maintenance and Contributes to the Pathogenesis of Murine Models of Lupus. J Immunol. 2016;196(11):4477-86.
28. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nature genetics. 2014;46(8):812-4.
29. Mitsuyama K, Matsumoto S, Masuda J, Yamasaki H, Kuwaki K, Takedatsu H, et al. Therapeutic strategies for targeting the IL-6/STAT3 cytokine signaling pathway in inflammatory bowel disease. Anticancer Research. 2007;27(6A):3749-56.
30. Miyoshi K, Takaishi M, Nakajima K, Ikeda M, Kanda T, Tarutani M, et al. Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor. Journal of Investigative Dermatology. 2011;131(1):108-17.
31. Park JS, Kwok SK, Lim MA, Kim EK, Ryu JG, Kim SM, et al. STA‐21, a promising STAT‐3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis & rheumatology. 2014;66(4):918-29.
32. Edwards LJ, Mizui M, Kyttaris V. Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice. Clinical immunology. 2015;158(2):221-30.
33. Wang R, Cai J, Chen K, Zhu M, Li Z, Liu H, et al. STAT3-NAV2 axis as a new therapeutic target for rheumatoid arthritis via activating SSH1L/Cofilin-1 signaling pathway. Signal Transduction and Targeted Therapy. 2022;7(1):209.
34. Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, et al. Interleukin‐6 and soluble interleukin‐6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast‐like cell formation. Journal of Bone and Mineral Research. 1996;11(1):88-95.
35. Goropevšek A, Holcar M, Pahor A, Avčin T. STAT signaling as a marker of SLE disease severity and implications for clinical therapy. Autoimmunity Reviews. 2019;18(2):144-54.
36. Haas U, Sczakiel G, Laufer S. MicroRNA-mediated regulation of gene expression is affected by disease-associated SNPs within the 3′-UTR via altered RNA structure. RNA Biology. 2012;9(6):924-37.
37. Zandi M, Moghaddam VA, Salehi Z, Mashayekhi F, Dalili S. The Impact of STAT3 rs1053005 Variation on Type 1 Diabetes Mellitus Susceptibility: Association Study and in Silico Analysis. Immunological Investigations. 2022:1-12.
38. Davidson SI, Liu Y, Danoy PA, Wu X, Thomas GP, Jiang L, et al. Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese. Annals of the rheumatic diseases. 2011;70(2):289-92.
39. Stypińska B, Olesińska M, Pawlik A, Paradowska-Gorycka A. Lack of significant association between selected STAT3 polymorphisms and rheumatoid arthritis in the Polish population. Reumatologia/Rheumatology. 2018;56(2):73-9.
40. Kotulska A, Kopeć-Mędrek M, Grosicka A, Kubicka M, Kucharz EJ. Correlation between erythrocyte sedimentation rate and C-reactive protein level in patients with rheumatic diseases. Reumatologia. 2015;53(5):243-6.
41. Kay J, Morgacheva O, Messing SP, Kremer JM, Greenberg JD, Reed GW, et al. Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year. Arthritis Research & Therapy. 2014;16(1):R40.
42. Cylwik B, Chrostek L, Gindzienska-Sieskiewicz E, Sierakowski S, Szmitkowski M. Relationship between serum acute-phase proteins and high disease activity in patients with rheumatoid arthritis. Advances in medical sciences. 2010;55(1):80-5.
43. Yoshida N, He F, Kyttaris VC. T cell–specific STAT3 deficiency abrogates lupus nephritis. Lupus. 2019;28(12):1468-72.
| Files | ||
| Issue | Vol 21 No 6 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i6.11523 | |
| Keywords | ||
| MicroRNAs Rheumatoid arthritis Single nucleotide polymorphisms STAT3 | ||
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How to Cite
1.
Salehi A, Hazrati E, Ranjbar H, Behroozi J, Pakzad B, Mousavi M, Mousavi M, Hossein Balam M, Salesi M. Importance of STAT3 Polymorphisms on the Risk and Clinical Characteristics of Rheumatoid Arthritis. Iran J Allergy Asthma Immunol. 2022;21(6):638-645.
