Polymorphisms in CTLA4 Influence Incidence of Drug-Induced Liver Injury after Renal Transplantation in Chinese Recipients

Yifeng Guo,Jianxin Qiu,Yu Fan,Fang Guo,Junwei Gao,Yong Liu,Mathias Toft

doi:10.1371/journal.pone.0051723

Abstract

Genetic polymorphisms in cytotoxic T lymphocyte-associated antigen 4 (CTLA4) play an influential role in graft rejection and the long-term clinical outcome of organ transplantation. We investigated the association of 5 CTLA4 single-nucleotide polymorphisms (SNPs) (rs733618 C/T, rs4553808 A/G, rs5742909 C/T, rs231775 A/G, and rs3087243 G/A) with drug-induced liver injury (DILI) in Chinese renal transplantation (RT) recipients. Each recipient underwent a 24-month follow-up observation for drug-induced liver damage. The CTLA4 SNPs were genotyped in 864 renal transplantation recipients. A significant association was found between the rs231775 genotype and an early onset of DILI in the recipients. Multivariate analyses revealed that a risk factor, recipient rs231775 genotype (p = 0.040), was associated with DILI. Five haplotypes were estimated for 4 SNPs (excluding rs733618); the frequency of haplotype ACGG was significantly higher in the DILI group (68.9%) than in the non-DILI group (61.1%) (p = 0.041). In conclusion, CTLA4 haplotype ACGG was partially associated with the development of DILI in Chinese kidney transplant recipients. The rs231775 GG genotype may be a risk factor for immunosuppressive drug-induced liver damage.

Highlights

Immunosuppressive therapy is usually administered as a triple regimen, such as cyclosporine A (CsA)/ tacrolimus (TAC)+mycophenolate mofetil (MMF)+prednisone (Pred)
Twenty-three patients were diagnosed as having drug-induced liver injury within the first month after operation; 26, 22 and 19 cases presented with DILI between 2 and 6 months, 7 and months and and 24 months after operation, respectively
Immunosuppressive therapy is usually administered as a triple regimen and typically includes cyclosporine A (CsA)/tacrolimus (TAC)+mycophenolate mofetil (MMF)+prednisone (Pred)

Summary

Introduction

Immunosuppressive therapy is usually administered as a triple regimen, such as cyclosporine A (CsA)/ tacrolimus (TAC)+mycophenolate mofetil (MMF)+prednisone (Pred). The triple regimen is favored because it produces a more effective immunosuppression and lessens the drug-induced damages or side effects. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is a key element in the immune system that induces immune tolerance and is one of the critical negative regulators of the T cell-mediated immune response [6]. It is expressed constitutively on the surface of regulatory T cells (Tregs) and is detectable on approximately 50% of Tregs; it is only found on ,1% of naive helper T cells [7].

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Conclusion