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Influence of cytotoxic T lymphocyte antigen 4 genetic variants on acute rejection in kidney transplant patients: precision medicine perspective

  • Research article
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Journal of Diabetes & Metabolic Disorders Aims and scope Submit manuscript

Abstract

Background

The most effective and common treatment for end-stage renal disease is kidney transplantation.

The personalized approach to kidney transplantation, which utilizes precision medicine principles, determines distinctive genomics characteristics of candidates/recipients that must be taken into account. Cytotoxic T lymphocyte associated protein 4 (CTLA4) may be a suitable candidate gene for studying allograft rejection. The aim of this study was to understand whether we can consider two common variants of the CTLA4 gene as a risk factor of transplant rejection in a group of Iranian population.

Methods

Totally, 169 kidney transplant recipients, including acute rejections (N=39) and non-rejection (N=130) groups who underwent transplantation were included in this study. The genotyping of rs5742909 (−318C/T) and rs231775 (+49A/G) variants of the CTLA4 gene were performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique.

Results

The AG genotype frequency of rs231775 variant was the same in both patients with and without a history of rejection while, none of those groups had homozygote genotype. In rs5742909, both CT and TT frequencies of patients with rejected transplant were lower than patients with a normal outcome.

Conclusions

The results of the presented study suggest that rs231775 and rs5742909 of CTLA4 genetic variants are not linked to acute rejection who underwent kidney transplantation. So, these variants cannot be considered as risk factors of acute allograft rejection in a group of Iranian renal transplantation recipients. However, the transplantation precision medicine may be an important area for the improvement of patients outcome as the precision medicine has already entered clinical practice in kidney transplantation.

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Data availability

This project’s data will be open to the public.

Abbreviations

AR:

allograft rejection

CTLA4:

cytotoxic T lymphocyte associated protein 4

SNP:

single nucleotide polymorphism

PCR-RFLP:

polymerase chain reaction-restriction fragment length polymorphism

SD:

standard deviation

BUN:

blood urea nitrogen

References

  1. Krichen H, Sfar I, Kacem HH, Bardi R, Jendoubi-Ayed S, Makhlouf M, et al., editors. repeat in the 3′ untranslated region of the CTLA-4 gene and susceptibility to acute allograft rejection in Tunisian renal transplantation. Transplant Proc. 2010;42:4314–7.

  2. Alegre M-L, Frauwirth KA, Thompson CB. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol. 2001;1(3):220.

    Article  CAS  Google Scholar 

  3. Marson A, Housley WJ, Hafler DA. Genetic basis of autoimmunity. J Clin Investig. 2015;125(6):2234–41.

    Article  Google Scholar 

  4. Orrù V, Steri M, Sole G, Sidore C, Virdis F, Dei M, et al. Genetic variants regulating immune cell levels in health and disease. Cell. 2013;155(1):242–56.

    Article  Google Scholar 

  5. Van Gelder T, Van Schaik RH, Hesselink DA. Pharmacogenetics and immunosuppressive drugs in solid organ transplantation. Nat Rev Nephrol. 2014;10(12):725–31.

    Article  Google Scholar 

  6. Willis JC, Lord GM. Immune biomarkers: the promises and pitfalls of personalized medicine. Nat Rev Immunol. 2015;15(5):323–9.

    Article  CAS  Google Scholar 

  7. Gautreaux MD, Freedman BI. Genotypic variation and outcomes in kidney transplantation: donor and recipient effects. Kidney Int. 2013;84(3):431–3.

    Article  Google Scholar 

  8. Ueda H, Howson JM, Esposito L, Heward J, Chamberlain G, Rainbow DB, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423(6939):506.

    Article  CAS  Google Scholar 

  9. Kristiansen O, Larsen Z, Pociot F. CTLA-4 in autoimmune diseases–a general susceptibility gene to autoimmunity? Genes Immun. 2000;1(3):170.

    Article  CAS  Google Scholar 

  10. Kalantari T, Mostafavi H, Pezeshki A, Farjadian S, Doroudchi M, Yeganeh F, et al. Exon-1 polymorphism of ctla-4 gene in Iranian patients with Graves' disease. Autoimmunity. 2003;36(5):313–6.

    Article  CAS  Google Scholar 

  11. Wiśniewski A, Kusztal M, Magott-Procelewska M, Klinger M, Jasek M, Łuszczek W, et al., editors. Possible association of cytotoxic T-lymphocyte antigen 4 gene promoter single nucleotide polymorphism with acute rejection of allogeneic kidney transplant. Transplant Proc. 2006;38:56–8.

  12. Howard TD, Postma DS, Hawkins GA, Koppelman GH, Zheng SL, Wysong AK, et al. Fine mapping of an IgE-controlling gene on chromosome 2q: analysis of CTLA4 and CD28. J Allergy Clin Immunol. 2002;110(5):743–51.

    Article  CAS  Google Scholar 

  13. Domański1AB L, Bobrek-Lesiakowska1B K, Kłoda1E K, Pawlik2AD A, Safranow3C K, Kurzawski2D M, et al. The impact of rs231775 (+ 49AG) CTLA4 gene polymorphism on transplanted kidney function. Ann Transplant. 2012;17(3):29–35.

  14. Gao J-w, Guo Y-f, Fan Y, J-x Q, Bao E-d, Liu Y, et al. Polymorphisms in cytotoxic T lymphocyte associated antigen-4 influence the rate of acute rejection after renal transplantation in 167 Chinese recipients. Transpl Immunol. 2012;26(4):207–11.

    Article  CAS  Google Scholar 

  15. Bouqbis L, Izaabel H, Akhayat O, Perez-Lezaun A, Calafell F, Bertranpetit J, et al. Association of the CTLA4 promoter region (− 1661G allele) with type 1 diabetes in the south Moroccan population. Genes Immun. 2003;4(2):132.

    Article  CAS  Google Scholar 

  16. Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.

    Article  CAS  Google Scholar 

  17. Haimila K, Turpeinen H, Alakulppi NS, Kyllönen LE, Salmela KT, Partanen J. Association of genetic variation in inducible costimulator gene with outcome of kidney transplantation. Transplantation. 2009;87(3):393–6.

    Article  CAS  Google Scholar 

  18. Pd R, Pravica V, Hop W, Boor P, Metselaar HJ, Hutchinson IV, et al. Recipient ctla-4+ 49 G/G genotype is associated with reduced incidence of acute rejection after liver transplantation. Am J Transplant. 2003;3(12):1587–94.

    Article  Google Scholar 

  19. Gorgi Y, Sfar I, Abdallah TB, Abderrahim E, Ayed SJ, Aouadi H, et al., editors. Ctla-4 exon 1 (+ 49) and promoter (− 318) gene polymorphisms in kidney transplantation. Transplant Proc. 2006;38:2303–5.

  20. Kusztal M, Kościelska-Kasprzak K, Drulis-Fajdasz D, Magott-Procelewska M, Patrzałek D, Janczak D, et al. The influence of CTLA-4 gene polymorphism on long-term kidney allograft function in Caucasian recipients. Transplant Immunol. 2010;23(3):121–4.

    Article  CAS  Google Scholar 

  21. Kim H-J, Jeong K-H, Lee S-H, Moon J-Y, Lee T-w, Kang SW, et al. Polymorphisms of the CTLA4 gene and kidney transplant rejection in Korean patients. Transplant Immunol. 2010;24(1):40–4.

    Article  CAS  Google Scholar 

  22. Gendzekhadze K, Rivas-Vetencourt P, Montano RF. Risk of adverse post-transplant events after kidney allograft transplantation as predicted by CTLA-4+ 49 and TNF-α− 308 single nucleotide polymorphisms: a preliminary study. Transplant Immunol. 2006;16(3–4):194–9.

    Article  CAS  Google Scholar 

  23. Dmitrienko S, Hoar DI, Balshaw R, Keown PA. Immune response gene polymorphisms in renal transplant recipients. Transplantation. 2005;80(12):1773–82.

    Article  Google Scholar 

  24. Marder BA, Schröppel B, Lin M, Schiano T, Parekh R, Tomer Y, et al. The impact of costimulatory molecule gene polymorphisms on clinical outcomes in liver transplantation. Am J Transplant. 2003;3(4):424–31.

    Article  CAS  Google Scholar 

  25. Kouki T, Sawai Y, Gardine CA, Fisfalen M-E, Alegre M-L, DeGroot LJ. CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of graves’ disease. J Immunol. 2000;165(11):6606–11.

    Article  CAS  Google Scholar 

  26. Krichen H, Sfar I, Jendoubi-Ayed S, Makhlouf M, Rhomdhane TB, Bardi R, et al. Editors. Genetic polymorphisms of immunoregulatory proteins in acute renal allograft rejection. Transplant Proc. 2006;38(7):2303–5.

    Article  Google Scholar 

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Acknowledgments

The authors acknowledge all subjects that generously has agreed to participate in this study.

Author information

Authors and Affiliations

  1. Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

    Andia Taleb, Mohammad Samzadeh & Mandana Hasanzad

  2. Department of Community Medicine, Zabol University of Medical Sciences, Zabol, Iran

    Mahdi Afshari

  3. Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

    Negar Sarhangi & Mandana Hasanzad

  4. Urology Nephrology Research Center, Shahid Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mohsen Nafar

Authors
  1. Andia Taleb
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  2. Mahdi Afshari
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  4. Negar Sarhangi
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Contributions

MH managed the project and provided guidance to the research; AT and NS drafted the manuscript and performed lab genotyping; MA performed the statistical analysis; MS sample collection; MN provided clinical guidance to the research. All authors contributed to and approved the final version of the manuscript.

Corresponding author

Correspondence to Mandana Hasanzad.

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Competing of interest

There are no conflicts of interest declared by the authors.

Consent for publication

All patients signed written consent forms and the study was approved by the ethical committee.

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Taleb, A., Afshari, M., Samzadeh, M. et al. Influence of cytotoxic T lymphocyte antigen 4 genetic variants on acute rejection in kidney transplant patients: precision medicine perspective. J Diabetes Metab Disord 21, 69–75 (2022). https://doi.org/10.1007/s40200-021-00936-7

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  • DOI: https://doi.org/10.1007/s40200-021-00936-7

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