Association of Gene Polymorphisms in CXC Chemokine Receptor 5 with Rheumatoid Arthritis Susceptibility
Abstract
Rheumatoid arthritis (RA) is caused by complicated interactions between genes and the environment. CXC chemokine receptor 5 (CXCR5) is required for B and T follicular helper cell migration and humoral immunity generation. Therefore, this study aimed to assess whether polymorphisms of the CXCR5 gene are implicated in RA development and progression.
This case-control study enrolled 285 RA patients and 291 healthy controls. The polymerase chain reaction-ligase detection reaction method was used to genotype rs630923, rs497916, rs3922, and rs676925 in the CXCR5 gene. Epidemiological, clinical, and laboratory data were collected retrospectively.
The rs630923 A allele was associated with a higher risk of RA (AOR [adjusted odds ratio]=2.00, 95% confidence interval [CI] =1.14–3.53). However, in the RA group, the frequency of the rs497916 T allele was lower (AOR=0.69, 95% CI=0.51–0.93). Regarding rs3922, AG+GG genotype carriers were at a significantly lower risk for RA than AA genotype carriers (AOR=0.70, 95% CI=0.49–0.99). In the RA group, we found that the different genotypes were significantly associated with specific laboratory values, including rheumatoid factor, total bilirubin, total cholesterol, low-density lipoprotein cholesterol, and alkaline phosphatase.
This is the first report indicating that CXCR5 polymorphisms were associated with RA susceptibility. These findings lead to a rising possibility of identifying RA-susceptible individuals based on genetic markers.
1. Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis: A Review. JAMA. 2018;320(13):1360-72.
2. Figus FA, Piga M, Azzolin I, McConnell R, Iagnocco A. Rheumatoid arthritis: Extra-articular manifestations and comorbidities. Autoimmun Rev. 2021;20(4):102776.
3. Houge IS, Hoff M, Thomas R, Videm V. Mortality is increased in patients with rheumatoid arthritis or diabetes compared to the general population - the Nord-Trøndelag Health Study. Sci Rep. 2020;10(1):3593.
4. Choi IA, Lee JS, Song YW, Lee EY. Mortality, disability, and healthcare expenditure of patients with seropositive rheumatoid arthritis in Korea: A nationwide population-based study. PLoS One. 2019;14(1):e0210471.
5. Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6(1):15-9.
6. Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):3–18.
7. Weyand CM, Goronzy JJ. The immunology of rheumatoid arthritis. Nat Immunol. 2021;22(1):10–18.
8. Paradowska-Gorycka A, Jurkowska M, Felis-Giemza A, Romanowska-Próchnicka K, Manczak M, Maslinski S, et al. Genetic polymorphisms of Foxp3 in patients with rheumatoid arthritis. J Rheumatol. 2015;42(2):170–80.
9. Mikhaylenko DS, Nemtsova MV, Bure IV, Kuznetsova EB, Alekseeva EA, Tarasov VV, et al. Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response. Int J Mol Sci. 2020;21(14):4911.
10. Van der Pouw Kraan TCTM, van Gaalen FA, Kasperkovitz PV, Verbeet NL, Smeets TJM, Kraan MC, et al. Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum. 2003;48(8):2132–45.
11. Rosenberg Jr EM, Herrington J, Rajasekaran D, Murphy JW, Pantouris G, Lolis EJ. The N-terminal length and side-chain composition of CXCL13 affect crystallization, structure and functional activity. Acta Crystallogr Sect D Struct Biol. 2020;76(Pt 10):1033–49.
12. Moser B. CXCR5, the defining marker for follicular B helper T (TFH) cells. Front Immunol. 2015;6:296.
13. Makhlouf MM, Radwan ER, Khorshed OM, Fathi LM, Elmasry MM. CXC Chemokine Receptor Type 5 Gene Polymorphisms in a Cohort of Egyptian Patients with Diffuse Large B-Cell Lymphoma. Pathobiology. 2021;88(3):211–7.
14. Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res Ther. 2012;14(6):R255.
15. Schmutz C, Hulme A, Burman A, Salmon M, Ashton B, Buckley C, et al. Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5. Arthritis Res Ther. 2005;7(2):217–29.
16. Niu Q, Huang ZC, Wu XJ, Jin YX, An YF, Li YM, et al. Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis. Arthritis Res Ther. 2018;20(1):200-9.
17. Moschovakis GL, Bubke A, Friedrichsen M, Falk CS, Feederle R, Förster R. T cell specific Cxcr5 deficiency prevents rheumatoid arthritis. Sci Rep. 2017;7(1):8933-9.
18. Mitkin NA, Muratova AM, Schwartz AM, Kuprash DV. The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced cxcr5 promoter activity in B-cell lymphoblastic cell lines. Front Immunol. 2016;7:515.
19. Lill CM, Schjeide BMM, Graetz C, Ban M, Alcina A, Ortiz MA, et al. MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis. Brain. 2013;136(Pt 6):1778–82.
20. Xia ZL, Qin QM, Zhao QY. A genetic link between CXCR5 and IL2RA gene polymorphisms and susceptibility to multiple sclerosis. Neurol Res. 2018;40(12):1040–1047.
21. Duan Z, Chen X, Liang Z, Zeng Y, Zhu F, Long L, et al. Genetic polymorphisms of CXCR5 and CXCL13 are associated with non-responsiveness to the hepatitis B vaccine. Vaccine. 2014;32(41):5316–22.
22. Wu Y, Fan J, Liao G, Xia M, Jiang D, Peng J, et al. Genetic variations in the CXCR5 gene decrease the risk of clinical relapse after discontinuation of nucleos(t)ide analogue therapy in patients with chronic hepatitis B. Infect Genet Evol. 2020;78:104124.
23. Jiang J, Karimi O, Ouburg S, Champion CI, Khurana A, Liu G, et al. Interruption of CXCL13-CXCR5 Axis Increases Upper Genital Tract Pathology and Activation of NKT Cells following Chlamydial Genital Infection. PLoS One. 2012;7(11):e47487.
24. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;62(9):2569–81.
25. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.
26. Fleischmann RM, van der Heijde D, Gardiner P V, Szumski A, Marshall L, Bananis E. DAS28-CRP and DAS28-ESR cut-offs for high disease activity in rheumatoid arthritis are not interchangeable. RMD open. 2017;3(1):e000382.
27. Aletaha D, Alasti F, Smolen JS. Rheumatoid factor, not antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17(1):229-31.
28. Pope JE, Choy EH. C-reactive protein and implications in rheumatoid arthritis and associated comorbidities. Semin Arthritis Rheum. 2021;51(1):219–29.
29. Orr CK, Najm A, Young F, McGarry T, Biniecka M, Fearon U, et al. The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis. Front Med (Lausanne). 2018;5:185-9.
30. Celiker R, Gökçe-Kutsal Y, Cindas A, Ariyürek M, Renda N, Koray Z, et al. Osteoporosis in rheumatoid arthritis: effect of disease activity. Clin Rheumatol. 1995;14(4):429–33.
31. Suzuki A, Yamamoto K. From genetics to functional insights into rheumatoid arthritis. Clin Exp Rheumatol. 2015;33 (4 Suppl 92):S40–S43.
32. Chen HY, Ma SL, Huang W, Ji L, Leung VHK, Jiang H, et al. The mechanism of transactivation regulation due to polymorphic short tandem repeats (STRs) using IGF1 promoter as a model. Sci Rep. 2016;6:38225.
33. Bentebibel SE, Schmitt N, Banchereau J, Ueno H. Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4 + T-cell subset specialized for B-cell help outside germinal centers. Proc Natl Acad Sci U S A. 2011;108(33):E488-497.
34. Sahebi L, Dastgiri S, Ansarin K, Sahebi R, Mohammadi SA. Study Designs in Genetic Epidemiology. ISRN Genet. 2013;2013:1–8.
35. Moschovakis GL, Bubke A, Friedrichsen M, Falk CS, Feederle R, Förster R. T cell specific Cxcr5 deficiency prevents rheumatoid arthritis. Sci Rep. 2017;7(1):8933-9.
36. Saad MN, Mabrouk MS, Eldeib AM, Shaker OG. Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: A systematic review and meta-analysis. J Adv Res. 2016;7(1):1–16.
37. Juping D, Yuan Y, Shiyong C, Jun L, Xiuxiu Z, Haijian Y, et al. Serum bilirubin and the risk of rheumatoid arthritis. J Clin Lab Anal. 2017;31(6):e22118.
38. Myasoedova E, Crowson CS, Kremers HM, Fitz-Gibbon PD, Therneau TM, Gabriel SE. Total cholesterol and LDL levels decrease before rheumatoid arthritis. Ann Rheum Dis. 2010;69(7):1310–4.
39. Nanke Y, Kotake S, Akama H, Kamatani N. Alkaline Phosphatase in Rheumatoid Arthritis Patients: Possible Contribution of Bone-Type ALP to the Raised Activities of ALP in Rheumatoid Arthritis Patients. Clin Rheumatol. 2002;21(3):198–202.
2. Figus FA, Piga M, Azzolin I, McConnell R, Iagnocco A. Rheumatoid arthritis: Extra-articular manifestations and comorbidities. Autoimmun Rev. 2021;20(4):102776.
3. Houge IS, Hoff M, Thomas R, Videm V. Mortality is increased in patients with rheumatoid arthritis or diabetes compared to the general population - the Nord-Trøndelag Health Study. Sci Rep. 2020;10(1):3593.
4. Choi IA, Lee JS, Song YW, Lee EY. Mortality, disability, and healthcare expenditure of patients with seropositive rheumatoid arthritis in Korea: A nationwide population-based study. PLoS One. 2019;14(1):e0210471.
5. Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;6(1):15-9.
6. Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):3–18.
7. Weyand CM, Goronzy JJ. The immunology of rheumatoid arthritis. Nat Immunol. 2021;22(1):10–18.
8. Paradowska-Gorycka A, Jurkowska M, Felis-Giemza A, Romanowska-Próchnicka K, Manczak M, Maslinski S, et al. Genetic polymorphisms of Foxp3 in patients with rheumatoid arthritis. J Rheumatol. 2015;42(2):170–80.
9. Mikhaylenko DS, Nemtsova MV, Bure IV, Kuznetsova EB, Alekseeva EA, Tarasov VV, et al. Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response. Int J Mol Sci. 2020;21(14):4911.
10. Van der Pouw Kraan TCTM, van Gaalen FA, Kasperkovitz PV, Verbeet NL, Smeets TJM, Kraan MC, et al. Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum. 2003;48(8):2132–45.
11. Rosenberg Jr EM, Herrington J, Rajasekaran D, Murphy JW, Pantouris G, Lolis EJ. The N-terminal length and side-chain composition of CXCL13 affect crystallization, structure and functional activity. Acta Crystallogr Sect D Struct Biol. 2020;76(Pt 10):1033–49.
12. Moser B. CXCR5, the defining marker for follicular B helper T (TFH) cells. Front Immunol. 2015;6:296.
13. Makhlouf MM, Radwan ER, Khorshed OM, Fathi LM, Elmasry MM. CXC Chemokine Receptor Type 5 Gene Polymorphisms in a Cohort of Egyptian Patients with Diffuse Large B-Cell Lymphoma. Pathobiology. 2021;88(3):211–7.
14. Liu R, Wu Q, Su D, Che N, Chen H, Geng L, et al. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res Ther. 2012;14(6):R255.
15. Schmutz C, Hulme A, Burman A, Salmon M, Ashton B, Buckley C, et al. Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5. Arthritis Res Ther. 2005;7(2):217–29.
16. Niu Q, Huang ZC, Wu XJ, Jin YX, An YF, Li YM, et al. Enhanced IL-6/phosphorylated STAT3 signaling is related to the imbalance of circulating T follicular helper/T follicular regulatory cells in patients with rheumatoid arthritis. Arthritis Res Ther. 2018;20(1):200-9.
17. Moschovakis GL, Bubke A, Friedrichsen M, Falk CS, Feederle R, Förster R. T cell specific Cxcr5 deficiency prevents rheumatoid arthritis. Sci Rep. 2017;7(1):8933-9.
18. Mitkin NA, Muratova AM, Schwartz AM, Kuprash DV. The A allele of the single-nucleotide polymorphism rs630923 creates a binding site for MEF2C resulting in reduced cxcr5 promoter activity in B-cell lymphoblastic cell lines. Front Immunol. 2016;7:515.
19. Lill CM, Schjeide BMM, Graetz C, Ban M, Alcina A, Ortiz MA, et al. MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis. Brain. 2013;136(Pt 6):1778–82.
20. Xia ZL, Qin QM, Zhao QY. A genetic link between CXCR5 and IL2RA gene polymorphisms and susceptibility to multiple sclerosis. Neurol Res. 2018;40(12):1040–1047.
21. Duan Z, Chen X, Liang Z, Zeng Y, Zhu F, Long L, et al. Genetic polymorphisms of CXCR5 and CXCL13 are associated with non-responsiveness to the hepatitis B vaccine. Vaccine. 2014;32(41):5316–22.
22. Wu Y, Fan J, Liao G, Xia M, Jiang D, Peng J, et al. Genetic variations in the CXCR5 gene decrease the risk of clinical relapse after discontinuation of nucleos(t)ide analogue therapy in patients with chronic hepatitis B. Infect Genet Evol. 2020;78:104124.
23. Jiang J, Karimi O, Ouburg S, Champion CI, Khurana A, Liu G, et al. Interruption of CXCL13-CXCR5 Axis Increases Upper Genital Tract Pathology and Activation of NKT Cells following Chlamydial Genital Infection. PLoS One. 2012;7(11):e47487.
24. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;62(9):2569–81.
25. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.
26. Fleischmann RM, van der Heijde D, Gardiner P V, Szumski A, Marshall L, Bananis E. DAS28-CRP and DAS28-ESR cut-offs for high disease activity in rheumatoid arthritis are not interchangeable. RMD open. 2017;3(1):e000382.
27. Aletaha D, Alasti F, Smolen JS. Rheumatoid factor, not antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17(1):229-31.
28. Pope JE, Choy EH. C-reactive protein and implications in rheumatoid arthritis and associated comorbidities. Semin Arthritis Rheum. 2021;51(1):219–29.
29. Orr CK, Najm A, Young F, McGarry T, Biniecka M, Fearon U, et al. The Utility and Limitations of CRP, ESR and DAS28-CRP in Appraising Disease Activity in Rheumatoid Arthritis. Front Med (Lausanne). 2018;5:185-9.
30. Celiker R, Gökçe-Kutsal Y, Cindas A, Ariyürek M, Renda N, Koray Z, et al. Osteoporosis in rheumatoid arthritis: effect of disease activity. Clin Rheumatol. 1995;14(4):429–33.
31. Suzuki A, Yamamoto K. From genetics to functional insights into rheumatoid arthritis. Clin Exp Rheumatol. 2015;33 (4 Suppl 92):S40–S43.
32. Chen HY, Ma SL, Huang W, Ji L, Leung VHK, Jiang H, et al. The mechanism of transactivation regulation due to polymorphic short tandem repeats (STRs) using IGF1 promoter as a model. Sci Rep. 2016;6:38225.
33. Bentebibel SE, Schmitt N, Banchereau J, Ueno H. Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4 + T-cell subset specialized for B-cell help outside germinal centers. Proc Natl Acad Sci U S A. 2011;108(33):E488-497.
34. Sahebi L, Dastgiri S, Ansarin K, Sahebi R, Mohammadi SA. Study Designs in Genetic Epidemiology. ISRN Genet. 2013;2013:1–8.
35. Moschovakis GL, Bubke A, Friedrichsen M, Falk CS, Feederle R, Förster R. T cell specific Cxcr5 deficiency prevents rheumatoid arthritis. Sci Rep. 2017;7(1):8933-9.
36. Saad MN, Mabrouk MS, Eldeib AM, Shaker OG. Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: A systematic review and meta-analysis. J Adv Res. 2016;7(1):1–16.
37. Juping D, Yuan Y, Shiyong C, Jun L, Xiuxiu Z, Haijian Y, et al. Serum bilirubin and the risk of rheumatoid arthritis. J Clin Lab Anal. 2017;31(6):e22118.
38. Myasoedova E, Crowson CS, Kremers HM, Fitz-Gibbon PD, Therneau TM, Gabriel SE. Total cholesterol and LDL levels decrease before rheumatoid arthritis. Ann Rheum Dis. 2010;69(7):1310–4.
39. Nanke Y, Kotake S, Akama H, Kamatani N. Alkaline Phosphatase in Rheumatoid Arthritis Patients: Possible Contribution of Bone-Type ALP to the Raised Activities of ALP in Rheumatoid Arthritis Patients. Clin Rheumatol. 2002;21(3):198–202.
| Files | ||
| Issue | Vol 21 No 5 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i5.11041 | |
| Keywords | ||
| CXC chemokine receptor 5 Disease susceptibility Rheumatoid arthritis Single nucleotide polymorphism | ||
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How to Cite
1.
Su Z, Chen L, Niu Q, Yang B, Huang Z. Association of Gene Polymorphisms in CXC Chemokine Receptor 5 with Rheumatoid Arthritis Susceptibility. Iran J Allergy Asthma Immunol. 2022;21(5):537-548.
