Evaluation of the -318C/T (rs5742909) CTLA4 gene polymorphism influence on kidney function after transplantation
Keywords:
CTLA4, polymorphism, acute rejection, delayed graft function
Abstract
ABSTRACT
Introduction: CTLA-4 protein (Cytotoxic T Lymphocyte Antigen-4) is a molecule that plays a significant role in maintaining immunological homeostasis. Recent studies demonstrated an unequivocal proof that CTLA-4 has an inhibitory effect on immune response. CTLA4 gene has been identified with several single nucleotide polymorphisms which could change gene activity, consequently leading to structural protein change. This genetic variability is associated with acute rejection and delayed graft function as important indicators of kidney transplantation success.
Aim: The aim of this study was to evaluate the potential association of CTLA4 (rs5742909) polymorphisms with acute rejection and delayed graft function in patients with kidney transplant.
Material and methods: A total of 151 patient were included in this retrospective cohort study. Real-time polymerase chain reaction was used to determine the genotype which was then evaluated in relation to acute rejection and delayed graft function. Statistical significance was analyzed by Pearson's Chi-square and Fisher's exact test.
Results: The most frequent genotype among 151 patient was CC (80.8%), then CT (17.9%) and TT (1.3%). The frequency of C allele is 89.7% whereas the frequency of T allele is 10.3%. There was no statistically significant difference in CTLA4 genotype and allele distribution nor their linkage to acute rejection and delayed graft function. The evaluation of C or T allele carriers showed no statistically significant difference with respect to previously mentioned posttransplant complications.
Conclusion: In this study, no statistically significant association between -318C/T (rs5742909) CTLA4 polymorphism and AR/DGF was found.
References
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23. Chen X, Hu Z, Liu M, Li H, et al. (2018). Correlation between CTLA-4 and CD40 gene polymorphisms and their interaction in graves’ disease in a Chinese Han population. BMC Medical Genetics, 19(1), 171.
24. Wen YH, Lin WT, Wang WT, Chiueh TS, Chen DP (2019). Association of CTLA4 gene polymorphism with transfusion reaction after infusion of leukoreduced blood component. Journal of Clinical Medicine, 8(11), 1961.
25. Guo Y, Gao J, Gao S, Shang M, Guo F (2016). Effect of CTLA-4 gene polymorphisms on longterm kidney allograft function in Han Chinese recipients. Oncotarget, 7(17), 23088–23095.
26. Ruhi Ç, Sallakçi N, Yeğin O, Süleymanlar G, Ersoy FF (2015). The influence of CTLA-4 single nucleotide polymorphisms on acute kidney allograft rejection in Turkish patients. Clinical Transplantation, 29(7), 612–618.
27. Kim HJ, Jeong KH, Lee SH, Moon JY, Lee T, Kang SW, et al. (2010). Polymorphisms of the CTLA gene and kidney transplant rejection in Korean patients. Transplant Immunology, 24(1), 40– 44.
28. Marder BA, Schröppel B, Lin M, Schiano T, Parekh R, Tomer Y, et al. (2003). The impact of costimulatory molecule gene polymorphisms on clinical outcomes in liver transplantation: Costimulation polymorphisms and liver transplantation. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 3(4), 424–431.
29. Rodriguez S, Gaunt TR, Day INM (2009). Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. American Journal of Epidemiology, 169(4), 505–514.
30. Mitsuiki N, Schwab C, Grimbacher B (2019). What did we learn from CTLA-4 insufficiency on the human immune system? Immunological Reviews, 287(1), 33–49.
31. Domański L, Bobrek-Lesiakowska K, Kłoda K, Pawlik A, Safranow K, et al. (2012). The impact of rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function. Annals of Transplantation: Quarterly of the Polish Transplantation Society, 17(3), 29–32.
32. Guo YF, Qiu JX, Guo F, Liu Y, Shang MH (2015). CTLA4 polymorphisms and de novo malignancy risk after renal transplantation in Chinese recipients. BioMed Research International, 2015, 986780.
33. Misra, M. K., Kapoor, R., Pandey, S. K., Sharma, R. K., Agrawal, S. (2014). Association of CTLA- 4 gene polymorphism with end-stage renal disease and renal allograft outcome. Journal of Interferon & Cytokine Research: The Official Journal of the International Society for Interferon and Cytokine Research, 34(3), 148–161.
34. Yang, C.-H., Chen, X.-X., Chen, L., Zheng, D.-H., Liu, Q.-S., Xie, W.-F, et al. (2017). Relationship between cytotoxic T-lymphocyte antigen 4 -318C/T (rs5742909) gene polymorphism and the risk of acute rejection in renal transplantation. Pediatric Transplantation, 21(7), e12920
2. Wolfe RA, Ashby VB, Milford EL, et al. (1999). Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. The New England Journal of Medicine, 341(23), 1725–1730.
3. Koo DD, Welsh KI, McLaren AJ, Roake JA, Morris PJ, Fuggle SV (1999). Cadaver versus living donor kidneys: impact of donor factors on antigen induction before transplantation. Kidney International, 56(4), 1551–1559.
4. Kamińska D, Kościelska-Kasprzak K, Chudoba P, et al. (2016). The influence of warm ischemia elimination on kidney injury during transplantation - clinical and molecular study. Scientific Reports, 6(1), 36118.
5. Malek M, Nematbakhsh M, 2015. Renal ischemia/reperfusion injury; from pathophysiology to treatment. Journal of Renal Injury Prevention, 4(2), 20–27.
6. Justiz Vaillant AA, Misra S, Fitzgerald BM, (2020). Acute Transplantation Rejection. In StatPearls. Treasure Island (FL): StatPearls Publishing.
7. Neri A, Scalzotto E, Corradi V, Caprara C, Salin A, Cannone M, et al. (2019). Acute rejection in kidney transplantation and the evaluation of associated polymorphisms (SNPs): the importance of sample size. Diagnosis (Berlin, Germany), 6(3), 287–295.
8. Roufosse C, Simmonds N, Clahsen-van Groningen M, Haas M, Henriksen KJ, Horsfield C, et al. (2018). A 2018 reference guide to the Banff Classification of renal Allograft Pathology. Transplantation, 102(11), 1795–1814.
9. Alexopoulos E, Leontsini M, Daniilidis M, et al. (1991). Differentiation between renal allograft rejection and cyclosporine toxicity: a clinicopathological study. American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation, 18(1), 108–115.
10. Dorr CR, Oetting WS, Jacobson PA, Israni AK (2018). Genetics of acute rejection after kidney transplantation. Transplant International: Official Journal of the European Society for Organ Transplantation, 31(3), 263–277.
11. Yarlagadda SG, Coca SG, et al. (2008). Marked variation in the definition and diagnosis of delayed graft function: a systematic review. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association - European Renal Association, 23(9), 2995–3003.
12. Koo DD, Welsh KI, McLaren AJ, Roake JA, Morris PJ, Fuggle SV (1999). Cadaver versus living donor kidneys: impact of donor factors on antigen induction before transplantation. Kidney International, 56(4), 1551–1559.
13. Abbas AK, Lichtman AHH, Pillai S (2015). Basic immunology: Functions and disorders of the immune system (5th ed.). Philadelphia, PA: Elsevier - Health Sciences Division.
14. Rudd CE, Taylor A, Schneider H (2009). CD28 and CTLA-4 coreceptor expression and signal transduction. Immunological Reviews, 229(1), 12–26.
15. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995). Loss of CTLA- 4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity, 3(5), 541–547.
16. Slavcheva E, Albanis E, Jiao Q, Tran H, Bodian C, et al. (2001). Cytotoxic t-lymphocyte antigen 4 gene polymorphisms and susceptibility to acute allograft rejection. Transplantation, 72(5), 935–940.
17. Krichen H, Sfar I, Hadj Kacem H, Bardi R, Jendoubi-Ayed S, Makhlouf M, et al. (2010). (AT) Repeat in the 3′ Untranslated Region of the CTLA-4 Gene and Susceptibility to Acute Allograft Rejection in Tunisian Renal Transplantation. Transplantation Proceedings, 42(10), 4314-4317.
18. Kim HJ, Jeong KH, Lee SH, Moon JY, et al. (2010). Polymorphisms of the CTLA4 gene and kidney transplant rejection in Korean patients. Transplant Immunology, 24(1), 40–44.
19. Leszek Domański, Katarzyna Bobrek-Lesiakowska, Karolina Kłoda, Andrzej Pawlik, et al. The impact of rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function. Annals of transplantation: quarterly of the Polish Transplantation Society, September 2012. 17 (3): 29-35
20. Sayegh MH, Turka LA (1998). The Role of T-Cell Costimulatory Activation Pathways in Transplant Rejection. New England Journal of Medicine, 338(25), 1813–1821.
21. Guo Y, Guo F, Wei C, Qiu J, Liu Y, Fang Y, et al. (2013). CTLA4 gene polymorphisms influence the incidence of infection after renal transplantation in Chinese recipients. PloS One, 8(8), e70824.
22. Fransen NL, Crusius JBA, Smolders J, et al. (2020). Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms. Brain Pathology (Zurich, Switzerland), 30(1), 106–119.
23. Chen X, Hu Z, Liu M, Li H, et al. (2018). Correlation between CTLA-4 and CD40 gene polymorphisms and their interaction in graves’ disease in a Chinese Han population. BMC Medical Genetics, 19(1), 171.
24. Wen YH, Lin WT, Wang WT, Chiueh TS, Chen DP (2019). Association of CTLA4 gene polymorphism with transfusion reaction after infusion of leukoreduced blood component. Journal of Clinical Medicine, 8(11), 1961.
25. Guo Y, Gao J, Gao S, Shang M, Guo F (2016). Effect of CTLA-4 gene polymorphisms on longterm kidney allograft function in Han Chinese recipients. Oncotarget, 7(17), 23088–23095.
26. Ruhi Ç, Sallakçi N, Yeğin O, Süleymanlar G, Ersoy FF (2015). The influence of CTLA-4 single nucleotide polymorphisms on acute kidney allograft rejection in Turkish patients. Clinical Transplantation, 29(7), 612–618.
27. Kim HJ, Jeong KH, Lee SH, Moon JY, Lee T, Kang SW, et al. (2010). Polymorphisms of the CTLA gene and kidney transplant rejection in Korean patients. Transplant Immunology, 24(1), 40– 44.
28. Marder BA, Schröppel B, Lin M, Schiano T, Parekh R, Tomer Y, et al. (2003). The impact of costimulatory molecule gene polymorphisms on clinical outcomes in liver transplantation: Costimulation polymorphisms and liver transplantation. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 3(4), 424–431.
29. Rodriguez S, Gaunt TR, Day INM (2009). Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. American Journal of Epidemiology, 169(4), 505–514.
30. Mitsuiki N, Schwab C, Grimbacher B (2019). What did we learn from CTLA-4 insufficiency on the human immune system? Immunological Reviews, 287(1), 33–49.
31. Domański L, Bobrek-Lesiakowska K, Kłoda K, Pawlik A, Safranow K, et al. (2012). The impact of rs231775 (+49AG) CTLA4 gene polymorphism on transplanted kidney function. Annals of Transplantation: Quarterly of the Polish Transplantation Society, 17(3), 29–32.
32. Guo YF, Qiu JX, Guo F, Liu Y, Shang MH (2015). CTLA4 polymorphisms and de novo malignancy risk after renal transplantation in Chinese recipients. BioMed Research International, 2015, 986780.
33. Misra, M. K., Kapoor, R., Pandey, S. K., Sharma, R. K., Agrawal, S. (2014). Association of CTLA- 4 gene polymorphism with end-stage renal disease and renal allograft outcome. Journal of Interferon & Cytokine Research: The Official Journal of the International Society for Interferon and Cytokine Research, 34(3), 148–161.
34. Yang, C.-H., Chen, X.-X., Chen, L., Zheng, D.-H., Liu, Q.-S., Xie, W.-F, et al. (2017). Relationship between cytotoxic T-lymphocyte antigen 4 -318C/T (rs5742909) gene polymorphism and the risk of acute rejection in renal transplantation. Pediatric Transplantation, 21(7), e12920
Published
2022/01/11
Section
Original Scientific Paper