Molecular Biology Reports

, Volume 39, Issue 9, pp 8701–8708 | Cite as

Polymorphisms in the cytotoxic T-lymphocyte antigen 4 gene and acute rejection risk in transplant recipients

  • Cheng-lin Zhu
  • Qiang Huang
  • Chen-hai Liu
  • Fang Xie


Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene polymorphisms have been reported to influence the risk for acute rejection (AR) in transplant recipients. However, the results still remain controversial and ambiguous. The objective of the current study was to conduct a meta-analysis investigating the association between polymorphisms in the CTLA-4 gene and the risk of AR in transplant recipients. Electronic searches for all publications were conducted on associations between this variant and acute rejection in Medline and Embase databases through November 2011. Crude odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to estimate the strength of the association. Three polymorphisms (+49 adenine/guanine [+49A/G], −318 cytosine/thymine [−318C/T], and the +6230G/A polymorphism [CT60]) in 18 case–control studies from ten articles were analyzed. This meta-analysis included 2,081 cases of transplant recipients in which 813 cases developed AR and 1,268 cases did not develop AR. The results indicated that there was no statistically significant association between the risk of AR and the +49A/G polymorphism or the −318C/T polymorphism (+49A/G: OR = 0.876, 95 % CI = 0.650–1.180 for GG vs. AA; OR = 1.121, 95 % CI = 0.911–1.379 for AG + GG vs. AA; −318C/T: OR = 0.397, 95 % CI = 0.138–1.143 for TT vs. CC; OR = 0.987, 95 %CI = 0.553–1.760 for CT + TT vs. CC). However, individuals who carried CT60 A allele might have a decreased risk of AR (AA vs. GG OR = 0.535, 95 % CI = 0.340–0.841, A vs. G OR = 0.759, 95 % CI = 0.612–0.914) in liver transplant recipients among Europeans, but because only two studies were included, so the result should be caution. In further stratified analyses for the +49A/G and the −318C/T polymorphisms, no obvious significant associations were found in subgroups of renal transplant recipients and Europeans, a reduced incidence of acute rejection was observed in liver transplant recipients that are homogenous for +49G (OR = 0.638, 95 % CI = 0.427–0.954 for GG vs. AA/AG), while this has not been observed in renal transplant recipients. Overall this meta-analysis suggests that +49A/G and the −318C/T polymorphisms in CTLA-4 may be not associated with the risk of rejection after organ transplantation, but CTLA +49A/G and +6230G/A polymorphisms may be associated with acute rejection after liver transplantation, not after renal transplantation. In future, more studies should be included to evaluate the association between +6230G/A polymorphism and AR risk.


Cytotoxic T-lymphocyte antigen 4 Polymorphism Acute rejection Meta-analysis 



This work was partly supported by the Grants from scientific and technological project of Anhui province (Code: 08010302189). We thank all the people who give the help for this study.

Conflict of interest

We declare that we have no conflict of interest.


  1. 1.
    Yu AS, Ahmed A, Keeffe EB (2002) Liver transplantation: involving patient selection criteria. Can J Gastroenterol 15(11):729–738CrossRefGoogle Scholar
  2. 2.
    Sayegh MH, Turka LA (1998) The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 338(25):1813–1821CrossRefPubMedGoogle Scholar
  3. 3.
    Marder B, Schroppel B, Murphy B (2003) Genetic variability and transplantation. Curr Opin Urol 13(2):81–89CrossRefPubMedGoogle Scholar
  4. 4.
    Sun T, Zhou Y, Yang M et al (2008) Functional genetic variations in cytotoxic T-lymphocyte antigen 4 and susceptibility to multiple types of cancer. Cancer Res 68(17):7025–7034CrossRefPubMedGoogle Scholar
  5. 5.
    Qi P, Ruan CP, Wang H et al (2010) CTLA-4 +49A > G polymorphism is associated with the risk but not with the progression of colorectal cancer in Chinese. Int J Colorectal Dis 25(1):39–45CrossRefPubMedGoogle Scholar
  6. 6.
    Ghaderi A, Yeganeh F, Kalantari T et al (2004) Cytotoxic T lymphocyte antigen-4 gene in breast cancer. Breast Cancer Res Treat 86(1):1–7CrossRefPubMedGoogle Scholar
  7. 7.
    Ligers A, Teleshova N, Masterman T et al (2001) CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun 2(3):145–152CrossRefPubMedGoogle Scholar
  8. 8.
    Ueda H, Howson JM, Esposito L et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423(6939):506–511CrossRefPubMedGoogle Scholar
  9. 9.
    Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10:101–129CrossRefGoogle Scholar
  10. 10.
    Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Nat Cancer Inst 22:719–748PubMedGoogle Scholar
  11. 11.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefPubMedGoogle Scholar
  12. 12.
    Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J (2005) A method for meta-analysis of molecular association studies. Stat Med 24:1291–1306CrossRefPubMedGoogle Scholar
  13. 13.
    Azarpira N, Malekhosseini SA, Aghdaie MH et al (2010) CTLA4 CT60A/G polymorphism in liver transplant recipients. Exp Clin Transpl 8(3):210–213Google Scholar
  14. 14.
    Haimila K, Turpeinen H, Alakulppi NS et al (2009) Association of genetic variation in inducible costimulator gene with outcome of kidney transplantation. Transplantation 87(3):393–396CrossRefPubMedGoogle Scholar
  15. 15.
    Kusztal M, Koscielska-Kasprzak K, Drulis-Fajdasz D et al (2010) The influence of CTLA-4 gene polymorphism on long-term kidney allograft function in Caucasian recipients. Transpl Immunol 23(3):121–124CrossRefPubMedGoogle Scholar
  16. 16.
    Krichen H, Sfar I, Jendoubi-Ayed S et al (2009) Genetic polymorphisms of immunoregulatory proteins in acute renal allograft rejection. Transpl Proc 41(8):3305–3307CrossRefGoogle Scholar
  17. 17.
    Krichen H, Sfar I, Hadj kacem H 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. Transpl Proc 42(10):4314–4317CrossRefGoogle Scholar
  18. 18.
    de Reuver P, Pravica V, Hop W et al (2003) Recipient CTLA-4 +49 G/G genotype is associated with reduced incidence of acute rejection after liver transplantation. Am J Transpl 3(12):1587–1594CrossRefGoogle Scholar
  19. 19.
    Marder BA, Schroppel B, Lin M et al (2003) The impact of costimulatory molecule gene polymorphisms on clinical outcomes in liver transplantation. Am J Transpl 3(4):424–431CrossRefGoogle Scholar
  20. 20.
    Tapirdamaz O, Pravica V, Metselaar HJ et al (2006) Polymorphisms in the T cell regulatory gene cytotoxic T lymphocyte antigen 4 influence the rate of acute rejection after liver transplantation. Gut 55(6):863–868CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Muro M, Rojas G, Botella C et al (2008) CT60 A/G marker of the 3′-UTR of the CTLA4 gene and liver transplant. Transpl Immunol 18(3):246–249CrossRefPubMedGoogle Scholar
  22. 22.
    Dmitrienko S, Hoar DI, Balshaw R et al (2005) Immune response gene polymorphisms in renal transplant recipients. Transplantation 80(12):1773–1782CrossRefPubMedGoogle Scholar
  23. 23.
    Wisniewski A, Kusztal M, Magott-Procelewska M et al (2006) Possible association of cytotoxic T-lymphocyte antigen 4 gene promoter single nucleotide polymorphism with acute rejection of allogeneic kidney transplant. Transpl Proc 38(1):56–58CrossRefGoogle Scholar
  24. 24.
    Gorgi Y, Sfar I, Abdallah TB et al (2006) CTLA-4 exon 1 (+49) and promoter (−318) gene polymorphisms in kidney transplantation. Transpl Proc 38(7):2303–2305CrossRefGoogle Scholar
  25. 25.
    Gendzekhadze K, Rivas-Vetencourt P, Montano RF et al (2006) 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. Transpl Immunol 16(3–4):194–199CrossRefPubMedGoogle Scholar
  26. 26.
    Kim HJ, Jeong KH, Lee SH et al (2010) Polymorphisms of the CTLA4 gene and kidney transplant rejection in Korean patients. Transpl Immunol 24(1):40–44CrossRefPubMedGoogle Scholar
  27. 27.
    Slavcheva E, Albanis Ea, Jiao Q et al (2001) Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to acute allograft rejection. Transplantation 72(5):935–940CrossRefPubMedGoogle Scholar
  28. 28.
    Scheipers P, Reiser H (1998) Role of the CTLA-4 receptor in T cell activation and immunity. Physiologic function of the CTLA-4 receptor. Immunol Res 18(2):103CrossRefPubMedGoogle Scholar
  29. 29.
    Bernard D, Hansen JD, Du Pasquier L et al (2007) Costimulatory receptors in jawed vertebrates: conserved CD28, odd CTLA-4 and multiple BTLAs. Dev Comp Immunol 31(3):255–271CrossRefPubMedGoogle Scholar
  30. 30.
    Kouki T, Sawai Y, Gardine CA et al (2000) 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 165(11):6606–6611CrossRefPubMedGoogle Scholar
  31. 31.
    Donner H, Rau H, Walfish PG et al (1997) CTLA4 alanine-17 confers genetic susceptibility to Graves’ disease and to type 1 diabetes mellitus. J Clin Endocrinol Metab 82(1):143–146PubMedGoogle Scholar
  32. 32.
    Agarwal K, Jones DE, Daly AK et al (2000) CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis. J Hepatol 32(4):538–541CrossRefPubMedGoogle Scholar
  33. 33.
    Agarwal K, Czaja AJ, Jones DE et al (2000) Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis. Hepatology 31(1):49–53CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Cheng-lin Zhu
    • 1
  • Qiang Huang
    • 1
  • Chen-hai Liu
    • 1
  • Fang Xie
    • 1
  1. 1.Department of General SurgeryAnhui Provincial Hospital Affiliated with Anhui Medical UniversityAnhui ProvinceChina

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