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Association of Foxp3 Polymorphism With Allograft Outcome in Kidney Transplantation

  • Park, Hyewon (Department of Laboratory Medicine, Seoul National University College of Medicine) ;
  • Lee, Nuri (Department of Laboratory Medicine, Seoul National University College of Medicine) ;
  • In, Ji Won (Department of Laboratory Medicine, Seoul National University College of Medicine) ;
  • Roh, Eun Youn (Department of Laboratory Medicine, Seoul National University College of Medicine) ;
  • Park, Kyoung Un (Department of Laboratory Medicine, Seoul National University College of Medicine) ;
  • Shin, Sue (Department of Laboratory Medicine, Seoul National University College of Medicine) ;
  • Yang, Jaeseok (Transplantation Center, Seoul National University Hospital, Transplantation Research Institute, Seoul National University College of Medicine) ;
  • Song, Eun Young (Department of Laboratory Medicine, Seoul National University College of Medicine)
  • Received : 2016.11.02
  • Accepted : 2017.05.22
  • Published : 2017.09.01

Abstract

Background: Forkhead box P3 (Foxp3) is the most reliable marker for regulatory T cells, which play an important role in maintaining renal allograft tolerance. Recently, Foxp3 polymorphisms have been reported to be associated with graft outcome in kidney transplantation. We analyzed the association of Foxp3 polymorphisms with renal allograft outcome. Methods: Foxp3 polymorphisms (rs3761548 A/C, rs2280883 C/T, rs5902434 del/ATT, and rs2232365 A/G) were tested by PCR with sequence-specific primers (PCR-SSP) in 231 adult kidney transplantation recipients from 1996-2004 at Seoul National University Hospital. Results: Patients with the rs3761548 CC genotype showed better graft survival than those with the AC or AA genotype (log rank test, P =0.03). Patients with the rs3761548 CC genotype also showed a lower rate of recurrence of the original glomerular disease than those with the AC or AA genotype (P =0.01). The frequency of acute rejection (AR) in patients with the rs2280883 TT genotype was lower than that in patients with the rs2280883 CT or CC genotype (26.9% vs 53.3%, P =0.038). Patients with the rs2280883 TT genotype also showed better graft survival than those with the CT or CC genotype (P =0.03). Conclusions: Foxp3 rs3761548 CC and rs2280883 TT genotypes were associated with superior graft outcome of kidney transplantation. Further studies involving a larger number of patients are needed.

Keywords

Acknowledgement

Supported by : SNUH

References

  1. Yates PJ and Nicholson ML. The aetiology and pathogenesis of chronic allograft nephropathy. Transpl Immunol 2006;16:148-57. https://doi.org/10.1016/j.trim.2006.10.001
  2. Zheng XX, Sanchez-Fueyo A, Sho M, Domenig C, Sayegh MH, Strom TB. Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance. Immunity 2003;19:503-14. https://doi.org/10.1016/S1074-7613(03)00259-0
  3. Li XC and Turka LA. An update on regulatory T cells in transplant tolerance and rejection. Nat Rev Nephrol 2010;6:577-83. https://doi.org/10.1038/nrneph.2010.101
  4. Graca L, Cobbold SP, Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med 2002;195:1641-6. https://doi.org/10.1084/jem.20012097
  5. Nagahama K, Nishimura E, Sakaguchi S. Induction of tolerance by adoptive transfer of Treg cells. Methods Mol Biol 2007;380:431-42.
  6. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4: 330-6. https://doi.org/10.1038/ni904
  7. Oda JM, Hirata BK, Guembarovski RL, Watanabe MA. Genetic polymorphism in FOXP3 gene: imbalance in regulatory T-cell role and development of human diseases. J Genet 2013;92:163-71. https://doi.org/10.1007/s12041-013-0213-7
  8. He Y, Na H, Li Y, Qiu Z, Li W. Foxp3 rs3761548 polymorphism predicts autoimmune disease susceptibility: a meta-analysis. Hum Immunol 2013; 74:1665-71. https://doi.org/10.1016/j.humimm.2013.08.270
  9. Bestard O, Cruzado JM, Rama I, Torras J, Goma M, Seron D, et al. Presence of FoxP3+ regulatory T cells predicts outcome of subclinical rejection of renal allografts. J Am Soc Nephrol 2008;19:2020-6. https://doi.org/10.1681/ASN.2007111174
  10. Grimbert P, Mansour H, Desvaux D, Roudot-Thoraval F, Audard V, Dahan K, et al. The regulatory/cytotoxic graft-infiltrating T cells differentiate renal allograft borderline change from acute rejection. Transplantation 2007;83:341-6. https://doi.org/10.1097/01.tp.0000248884.71946.19
  11. Mansour H, Homs S, Desvaux D, Badoual C, Dahan K, Matignon M, et al. Intragraft levels of Foxp3 mRNA predict progression in renal transplants with borderline change. J Am Soc Nephrol 2008;19:2277-81. https://doi.org/10.1681/ASN.2008030254
  12. Krepsova E, Tycova I, Sekekova A, Wohlfahrt P, Hruba P, Striz I, et al. Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance. BMC Nephrol 2015;16:146. https://doi.org/10.1186/s12882-015-0141-2
  13. Iwase H, Kobayashi T, Kodera Y, Miwa Y, Kuzuya T, Iwasaki K, et al. Clinical significance of regulatory T-cell-related gene expression in peripheral blood after renal transplantation. Transplantation 2011;91:191-8. https://doi.org/10.1097/TP.0b013e3181ffbab4
  14. Muthukumar T, Dadhania D, Ding R, Snopkowski C, Naqvi R, Lee JB, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 2005;353:2342-51. https://doi.org/10.1056/NEJMoa051907
  15. Veronese F, Rotman S, Smith RN, Pelle TD, Farrell ML, Kawai T, et al. Pathological and clinical correlates of FOXP3+ cells in renal allografts during acute rejection. Am J Transplant 2007;7:914-22. https://doi.org/10.1111/j.1600-6143.2006.01704.x
  16. Qiu XY, Jiao Z, Zhang M, Chen JP, Shi XJ, Zhong MK. Genetic association of FOXP3 gene polymorphisms with allograft rejection in renal transplant patients. Nephrology (Carlton) 2012;17:423-30. https://doi.org/10.1111/j.1440-1797.2012.01561.x
  17. Engela AU, Boer K, Roodnat JI, Peeters AM, Eilers PH, Kal-van Gestel JA, et al. Genetic variants of FOXP3 influence graft survival in kidney transplant patients. Hum Immunol 2013;74:751-7. https://doi.org/10.1016/j.humimm.2013.02.008
  18. Misra MK, Mishra A, Pandey SK, Kapoor R, Sharma RK, Agrawal S. Association of functional genetic variants of transcription factor Forkhead Box P3 and Nuclear $Factor-{\kappa}B$ with end-stage renal disease and renal allograft outcome. Gene 2016;581:57-65. https://doi.org/10.1016/j.gene.2016.01.028
  19. Song EY, Park MH, Kang SJ, Park HJ, Kim BC, Tokunaga K, et al. HLA class II allele and haplotype frequencies in Koreans based on 107 families. Tissue Antigens 2002;59:475-86. https://doi.org/10.1034/j.1399-0039.2002.590604.x
  20. Chen X, Gan T, Liao Z, Chen S, Xiao J. Foxp3 (-/ATT) polymorphism contributes to the susceptibility of preeclampsia. PLoS One 2013;8:e59696. https://doi.org/10.1371/journal.pone.0059696
  21. Gao L, Li K, Li F, Li H, Liu L, Wang L, et al. Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients. J Dermatol Sci 2010;57:51-6. https://doi.org/10.1016/j.jdermsci.2009.09.010
  22. Wu Z, You Z, Zhang C, Li Z, Su X, Zhang X, et al. Association between functional polymorphisms of Foxp3 gene and the occurrence of unexplained recurrent spontaneous abortion in a Chinese Han population. Clin Dev Immunol 2012;2012:896458.
  23. Inoue N, Watanabe M, Morita M, Tomizawa R, Akamizu T, Tatsumi K, et al. Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases. Clin Exp Immunol 2010;162:402-6. https://doi.org/10.1111/j.1365-2249.2010.04229.x
  24. Hoogendoorn B, Coleman SL, Guy CA, Smith K, Bowen T, Buckland PR, et al. Functional analysis of human promoter polymorphisms. Hum Mol Genet 2003;12:2249-54. https://doi.org/10.1093/hmg/ddg246
  25. Coppo R, Amore A, Chiesa M, Lombardo F, Cirina P, Andrulli S, et al. Serological and genetic factors in early recurrence of IgA nephropathy after renal transplantation. Clin Transplant 2007;21:728-37.
  26. Andrc GM, Barbosa CP, Teles JS, Vilarino FL, Christofolini DM, Bianco B. Analysis of FOXP3 polymorphisms in infertile women with and without endometriosis. Fertil Steril 2011;95:2223-7. https://doi.org/10.1016/j.fertnstert.2011.03.033
  27. Zheng L, Wang X, Xu L, Wang N, Cai P, Liang T, et al. Foxp3 gene polymorphisms and haplotypes associate with susceptibility of Graves' disease in Chinese Han population. Int Immunopharmacol 2015;25:425-31. https://doi.org/10.1016/j.intimp.2015.02.020
  28. Owen CJ, Eden JA, Jennings CE, Wilson V, Cheetham TD, Pearce SH. Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population. J Mol Endocrinol 2006;37:97-104. https://doi.org/10.1677/jme.1.02072
  29. Eastell T; BSPAR Study Group, Hinks A, Thomson W. SNPs in the FOXP3 gene region show no association with Juvenile Idiopathic Arthritis in a UK Caucasian population. Rheumatology (Oxford) 2007;46:1263-5. https://doi.org/10.1093/rheumatology/kem129
  30. Fadel FI, Elshamaa MF, Salah A, Nabhan M, Rasheed M, Kamel S, et al. Fas/Fas Ligand pathways gene polymorphisms in pediatric renal allograft rejection. Transpl Immunol 2016;37:28-34. https://doi.org/10.1016/j.trim.2016.04.006
  31. Park H, Shin S, Park MH, Kim YS, Ahn C, Ha J, et al. Association of IL-17F gene polymorphisms with renal transplantation outcome. Transplant Proc 2014;46:121-3. https://doi.org/10.1016/j.transproceed.2013.05.015

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