• Are the Costimulatory Molecule Gene Polymorphisms (CTLA-4) Associated With Infection in Organ Transplantation? A Meta-Analysis
  • Mahdiyar Iravani Saadi,1,* Mingjum Jiang,2 Morteza Banakar,3 Fatemeh Mardani Valandani,4 Maryam Ahmadyan,5 Hossain Ali Rostamipour,6
    1. Hematology Research center Shiraz university Of medical sciences
    3. Hematology Research center Shiraz university Of medical sciences
    4. Hematology Research center Shiraz university Of medical sciences
    5. Hematology Research center Shiraz university Of medical sciences
    6. Hematology Research center Shiraz university Of medical sciences


  • Introduction: Polymorphisms in the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene, which may influence CTLA4’s role in regu-lating the immune response, have been postulated to affect disease susceptibility and chronicity in individuals with HBV infection; however, the results are still contentious. CD28, like CTLA4, binds to B7 family receptors (CD80 and CD86), but after being produced on T cells, it gives a posi-tive costimulatory signal for T-cell proliferation1,2. CTLA4 (cytotoxic T lymphocyte-associated antigen 4) is an impor-tant negative regulator of the T cell-mediated immune response and a vital component in the immune system’s induction of immunological tolerance3. It is also produced constitutively on the surface of regulatory T cells (Tregs); it may be detected on roughly 50% of Tregs but just 1% of naive helper T cells4. In mice, ligation of CTLA4 on Tregs leads to a considerable reduction in antigen-presenting cell presentation capability and effector T cell downregulation5. CTLA4 plays a critical function in the immune response’s downregulation.In 172 chronic HBV-infected individuals, Duan and col-leagues looked at the CTLA-4 49A/G and 318 T/C polymor-phisms. In chronic HBV-infected individuals, the AA genotype and A allele of the CTLA-4 49A/G polymorphisms, as well as the genotype CC of the CTLA-4 -318 C/T poly-morphisms, were observed more often6. Thio and colleagues discovered a link between the CTLA-4 49A/G gene and HBV infection clearance7. The rs231775 (+49A/G) single nucleotide polymorphism (SNP) is found inside the mole-cule’s signal peptide and affects full-length isoform expres-sion on the T cell surface. The rs3087243 (+6230G/A) SNP is discovered within the 39 untranslated regions of the CTLA-4 gene and has been linked to autoimmune disease susceptibility8. Furthermore, CTLA4 SNPs like 21772T/C (rs733618), +49A/G (rs231775), and +6230 G/A (rs3087243) have a role in graft rejection and the long-term clinical outcome of organ transplantation9,10–14. It has been proposed that the CTLA4 gene variant influences infection following juvenile heart transplantation. The SNP CTLA4 +49(rs231775) has been linked to late post-transplantation viral infection in pediatric heart transplant patients in the United States, according to Ohmann et al. The relevance of CTLA4 SNPs in T cell-mediated immunity and their connec-tion with infection following renal transplantation is uncer-tain. As a result, the goal of this study was to look at the links between infection and five CTLA4 SNPs (rs733618 C/T, rs4553808 A/G, rs5742909 C/T, rs231775 A/G, and rs3087243 G/A) in Chinese kidney transplant recipients.The SNP CTLA4 +49(rs231775) has been linked to late post-transplantation viral infection in pediatric heart trans-plant patients in the United States, according to Ohmann et al.15 Several studies have found that the CC genotype is related to viral illness and persistent HBV infection for the SNP rs5742909 C/T16. The SNPs rs5742909 and rs231775, on the other hand, did not show any statistically significant relationships in the research. This lack of correlation might be attributed to the small sample size and insufficient power to detect a link; also, the frequency of the G allele at the CTLA4 +49 (rs231775) locus is substantially greater in the Chinese population than in other populations17. This might suggest that genetic bias has little impact on infec-tion susceptibility. The CTLA4+49(rs231775)GG geno-type was also linked to enhanced interferon-c production following immunological activation, according to recent research.Several SNPs in the CTLA4 gene may affect gene expres-sion, leading to amino acid substitution and mRNA splicing, which might influence T-cell activation and, eventually, host immunological state. These genetic polymorphisms have been linked to post-transplant infections15,18, and they might lead to interindividual variances in immunotherapy targeting this protein. There are numerous polymorphic markers in the CTLA4 gene. The most commonly examined SNPs in the CTLA4 3′ untranslated region (UTR) are at locations 1722, 1661, 1147, 658, 318, + 49, and + 6230, as well as dinucleo-tide (AT)n repeats13,14,19,20. Cytomegalovirus (CMV) infec-tion is controlled in part by innate and adaptive immune responses. CTLA4 is a critical component of both the innate and adaptive immune systems. CTLA4 is a cell surface mol-ecule that is only found on CD4+ and CD8+ T lympho-cytes. CD4+ T cells have been found to be able to reduce initial systemic CMV infection21, limit persistent replication in specific organs22, and boost antibody responses23 in exper-imental CMV infection models. CD8+ cells, on the other hand, can protect immunocompromised people and animals from CMV infection by T cells by limiting the viral reactiva-tion from a state of delay.
  • Methods: A literature search was conducted using combinations of the keywords “CTLA-4 or cytotoxic T-lymphocyte anti-gen-4 associated AND polymorphism or SNP or single nucleotide polymorphisms or rs5742909 or rs733618 or rs4553808 or rs231775 or genotype AND organ Transplantation or Transplantation AND viral infection or bacterial infection” in PubMed, Google Scholar, Web of Science, EMBASE, Google Scholar, Wanfang, China National Knowledge Infrastructure (CNKI), Islamic World Science Citation Center (ISC), and Scientific Information Database (SID) databases. All research that looked at the link between organ transplantation gene polymorphisms and infection risk was gathered. The literature search has no language restrictions. To find possibly relevant papers, the reference lists of the eligible studies, reviews, and prio meta-analysis publications were manually examined. All procedures were carried out in accordance with the 1975 Helsinki Protocol and its subsequent amendments. It was also approved by the Ethics Committee of Shiraz University of Medical Sciences
  • Results: A total of 1,567 studies were found to be suitable after exten-sive database searches. In total, 513 publications were omit-ted due to duplicated records, 912 papers were excluded following the primary screening, and 154 papers were excluded after full-text evaluation after screening the col-lected studies based on inclusion criteria for the current meta-analysis. The methodological technique for including researc and obtaining important data from eligible papers are depicted in Fig. 1. Finally, nine studies found an association between viral infection and rs5742909, rs733618, rs4553808, and rs231775 polymorphisms in organ transplantatio .
  • Conclusion: This meta-analysis indicated that a significant correlation between CTLA4+49 (A/G- 231775) and CTLA4(rs5742909TT) gene poly-morphism with infection in organ transplantation risk was observed. Further studies involving gene–gene and gene–diet interactions should be conducted to investigate this association
  • Keywords: CTLA-4, transplantation, polymorphism