Significant association between FOXP3 gene polymorphism and steroid‐resistant acute rejection in living donor liver transplantation

Abstract

Previous studies have found that preferential accumulation of regulatory T (Treg) cells in liver allografts during acute cellular rejection (ACR) is associated with less severe rejection, suggesting a role of Treg cells in preventing excessive progress of ACR. We investigated the impact of single nucleotide polymorphisms (SNPs) in the Forkhead box P3 (FOXP3) gene, a master regulator gene of Treg cells, on ACR severity in liver transplant (LT) recipients. In total, 102 living donor LT patients were enrolled in this study and categorized into no rejection (n = 86), steroid‐sensitive acute rejection (SSAR; n = 11), and steroid‐resistant acute rejection (SRAR; n = 5). FOXP3 SNPs –3499 A/G (rs3761547), –3279 A/C (rs3761548), and –924 A/G (rs2232365) were genotyped using the polymerase chain reaction restriction fragment length polymorphism technique. T‐cell responses to allostimulation were evaluated by the mixed lymphocyte reaction assay. We found no statistical association between the FOXP3 SNP genotype frequencies and ACR incidence. However, significantly higher incidence of SRAR was observed in LT patients with the FOXP3 rs3761548 A/C+A/A genotype than in those with the C/C genotype (A/C+A/A versus C/C; no rejection, SSAR, SRAR, 85.71%, 0%, 14.29% versus 83.58%, 16.42%, 0%, respectively; P = 0.0005). The mixed lymphocyte reaction assay performed at the time of ACR diagnosis showed higher anti‐donor CD4+ T‐cell responses in patients carrying rs3761548 A/C+A/A than in those with the C/C genotype (P = 0.019). No significant association was observed between the incidence of SRAR and either rs3761547A/G or rs2232365 A/G. Infectious complications and overall survival were not related to FOXP3 SNPs. Conclusion: Our findings indicate that FOXP3 SNP rs3761548 A/C might be a predisposing factor for SRAR after liver transplantation. (Hepatology Communications 2017;1:406–420)

Impact of TBX21, GATA3, and FOXP3 gene polymorphisms on acute cellular rejection after liver transplantation

“…In contrast, the SNPs 2232365 and rs3761548 of the FOXP3 gene have been analyzed in different studies concerning graft rejection. In agreement with our results, Verma et al did not observe any association between SNP rs2232365 and acute cellular liver transplant rejection . But, this study reported an association between the genotypes −3279AA and −3279CA of the SNP rs3761548 and steroid‐resistant acute cellular rejection .…”

“…In agreement with our results, Verma et al did not observe any association between SNP rs2232365 and acute cellular liver transplant rejection . But, this study reported an association between the genotypes −3279AA and −3279CA of the SNP rs3761548 and steroid‐resistant acute cellular rejection . Yet, in this study liver grafted patients were not subdivided according to the time point of occurrence of acute cellular rejection.…”

Diminished circulating concentration of interleukin‐35 in Helicobacter pylori‐infected patients with peptic ulcer: Its association with FOXP3 gene polymorphism, bacterial virulence factor CagA, and gender of patients

“…As the SNP rs3761548 represents a polymorphism situated in the promoter region of FOXP3 gene, it could influence, directly or indirectly, the expression of FOXP3 protein in Treg cells. Indeed, the SNP rs3761548 is situated in the core GGGCGG sequence of the binding site for a transcription factor called specificity protein‐1 (Sp‐1) . The SNP rs3761548 was found to be capable of modulating the interaction of the Sp‐1 with the promoter of FOXP3 gene .…”

“…Indeed, a reduced FOXP3 expression was observed in subjects with AA genotype compared with individuals with AC and CC genotypes at SNP rs3761548 . Moreover, the AA genotype was introduced as a risk factor for a number of autoimmune diseases, allergic rhinitis, and allograft rejection . Thereby, the presence of the AA genotype or A allele at SNP rs3761548 may lead to a defect of the Treg cell activity.…”

“…The promoter is involved in initiation of transcription and therefore is among the major elements that control gene expression . Polymorphisms in the promoter region of FOXP3 may potentially alter gene expression by changing the binding specificity of transcription factors to their binding sites and by modifying the kinetics of transcription initiation, causing Treg cell dysfunction and consequently affecting the outcome of infectious and inflammatory diseases . The SNP −3279C/A (rs3761548) is among the polymorphisms located in the promoter region of FOXP3 gene .…”