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

<div><p>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.</p> </div

The distribution of haplotypes in 5 locus of CTLA-4 between DILI and non- DILI.

<p>DILI: Drug induced liver injury,</p>*<p>exclude the locus in rs 733618.</p

Diagnosis time of drug-induced liver injury after renal transplantation.

<p>Twenty-three patients were diagnosed 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 12 months and 13 and 24 months after operation, respectively.</p

Correlation between early onset of DILI and <i>CTLA4</i> genotypes in recipients.

<p>DILI: drug induced liver injury, CI: confidence intervals.</p>*<p>log-rank test.</p

Association between DILI and several risk factors.

<p>CsA: cyclosporine, MMF: mycophenolate mofetil, Pred: prednisone, TAC: tacolimous, AR: acute rejection, non-AR: non-acute rejection, DILI: drug induced liver injury.</p

The genotype distribution of the <i>CTLA4</i> polymorphisms in patients with DILI and non-DILI.

<p>DILI: drug induced liver injury, OR: odds ratio, CI: confidence intervals.</p

The allele distribution of <i>CTLA4</i> polymorphisms in patients with DILI and non-DILI.

<p>DILI: drug induced liver injury, OR: odds ratio, CI: confidence intervals.</p

PCR primers of the <i>CTLA4</i> SNP used in the study.

<p>AT: annealing temperature.</p

Association between <i>CTLA4</i> SNPs and early onset of drug-induced liver injury in renal transplantation.

<p>No statistical differences for rs733618 (Figure 2a), rs4553808 (Figure 2b), rs5742909 (Figure 2c) or rs3087243(Figure 2e) was found between DILI and non-DILI recipients. A significant difference (p = 0.039) was found between patients bearing the rs231775 GG genotype and those with the AA+AG genotypes using the log-rank test (Figure 2d).</p

Comparison of clinical characteristics between patients with DILI and non-DILI.

<p>CsA: cyclosporine, MMF: mycophenolate mofetil, Pred: prednisone, TAC: tacolimous, AR: acute rejection, non-AR: non-acute rejection, DILI: drug induced liver injury.</p