PXR单核苷酸多态性与肾移植受者环孢素所致肝损伤的相关性研究

Association of PXR polymorphisms with cyclosporine drug-induced hepatotoxicity in Chinese renal transplant recipients

目的:探讨肾移植受者中PXR基因多态性与环孢素A(cyclosporine, CsA)血谷浓度和CsA致肝损伤易感性的相关性。方法:将入组的188例肾移植受者分为CsA致肝损伤组(16例)和对照组(172例),采用多重PCR技术结合高通量二代测序技术对PXR基因的6个SNP位点(rs2276707 C>T、rs6784598 G>C、rs7643645 A>G、rs6771638 G>T、rs1523127 T>G、 rs3814055 C>T)进行基因分型,采用TDx血药浓度分析仪检测CsA血谷浓度,分析PXR基因多态性对CsA血谷浓度的影响,同时比较PXR基因型及单倍型在CsA致肝损伤组与对照组间分布差异。结果:rs1523127(P^(Dom)=0.048 5)、rs3814055(P^(Dom)=0.048 5)、rs6784598(P^(Dom)=0.021 1、P^(Add)=0.036 6)术后36个月时间点血谷浓度C_0有显著性差异。rs6784598(P^(Dom)=0.049 2、P^(Rec)=0.011 7、P^(Add)=0.005 3)、rs7643645(P^(Add)=0.025 7、P^(Dom)=0.027 4)、rs2276707(P^(Dom)=0.046 8)后12个月时间点间血谷浓度C_0有显著性差异;rs2276707(P^(Add)=0.049 1、P^(Dom)=0.023 9)术后7 d时间点有显著性差异。PXR基因各SNP位点的等位基因分布频率在CsA致肝损伤组与对照组间分布频率均无显著差异(P>0.05)。rs6771638位点的TG基因型在CsA致肝损伤组与对照组间的分布频率有显著差异(P=0.030),TG+TT基因型在肝损伤组的分布频率更低,是CsA致肝损伤的保护性因素。PXR基因的单倍型与CsA所致肝损伤无明显相关性(P>0.05)。结论:PXR rs1523127、rs3814055、rs6784598、rs7643645、rs2276707与肾移植受者CsA血谷浓度显著相关;PXR rs6771638 G>T与CsA所致肝损伤相关,是CsA所致肝损伤的保护性因素。

OBJECTIVE To investigate the association between PXR gene polymorphism and cyclosporine A(CsA)blood trough concentration and susceptibility to CsA-induced liver injury in renal transplant recipients.METHODS 188 cases of renal transplant recipients were divided into CsA-induced liver injury group(16 cases)and control group(172 cases).Six SNP loci(rs 2276707 C>T,rs 6784598 G>C,rs 7643645 A>G,rs 6771638 G>T,rs 1523127 T>G,rs 3814055 C>T)of PXR gene were genotyped by multiplex PCR combined with high-throughput second-generation sequencing.The trough concentration of CsA was detected by TDx plasma concentration analyzer.The effect of PXR gene polymorphism on trough concentration of CsA was analyzed.The distribution differences of PXR genotypes and haplotypes between CsA-induced liver injury group and control group were also compared.RESULTS There was a significant difference in blood trough concentration C0 at 36 months post surgery for rs 1523127(Pdom=0.048 5),rs 3814055(Pdom=0.048 5),and rs 6784598(Pdom=0.021 1,Padd=0.036 6).There was a significant difference in blood trough concentration C0 at 12 months post surgery for rs 6784598(Pdom=0.049 2,Prec=0.011 7,Padd=0.0053),rs 7643645(Padd=0.025 7,Pdom=0.027 4),and rs 2276707(Pdom=0.046 8);there was a significant difference at 7 days post surgery for rs 2276707(Pdd=0.049 1,Pdom=0.023 9).There was no significant difference in the allele distribution frequency of each SNP in the PXR gene between the CsA-induced liver injury group and the control group(P>0.05).The distribution frequency of TG genotype for rs 6771638 was statistically different between CsA-induced liver injury group and control group(P=0.030),and the distribution frequency of TG+TT genotype was lower in the liver injury group,which was a protective factor for CsA-induced liver injury.The haplotype of the PXR gene was not significantly associated with CsA-induced liver injury(P>0.05).CONCLUSION PXR rs 1523127,rs 3814055,rs 6784598,rs 7643645,rs 2276707 were significantly associated with CsA blood trough concentrations in renal transplant recipients;PXR rs 6771638 G>T was associated with CsA-induced liver injury and was a protective factor for CsA-induced liver injury.