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

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).