ABCC2基因多态性与肾移植受者环孢素所致肝功能异常的相关性研究

中国临床药理学与治疗学 ›› 2013, Vol. 18 ›› Issue (7): 778-784.

ABCC2基因多态性与肾移植受者环孢素所致肝功能异常的相关性研究

辛华雯¹, 刘慧明¹, 李元启², 黄晖², 赵丽², 余爱荣¹, 李罄¹, 吴笑春¹, 李维亮¹, 熊磊¹

¹广州军区武汉总医院临床药理科;
²湖北省药品(医疗器械)不良反应监测中心,武汉430070,湖北

收稿日期:2012-07-09 修回日期:2012-10-23 出版日期:2013-07-26 发布日期:2013-06-20
作者简介:辛华雯,女,主任医师,硕士生导师,研究方向:临床药理学。Tel: 027-68878688 E-mail: huawenxin@163.com
基金资助:
湖北省自然科学基金计划资助项目(2009CDB010)

Association of ABCC2 genetic polymorphism with liver disfunction induced by cyclosporine in Chinese renal transplant recipients

XIN Hua-wen¹, LIU Hui-ming¹, LI Yuan-qi², HUANG Hui², ZHAO Li², YU Ai-rong¹, LI Qing¹, WU Xiao-chun¹, LI Wei-liang¹, XIONG Lei¹

¹Department of Clinical Pharmacology, Wuhan General Hospital of Guangzhou Command;
²Monitering Center for Adverse Reaction of Drug and Medical Instrument of Hubei Province, Wuhan 430070, Hubei, China

Received:2012-07-09 Revised:2012-10-23 Online:2013-07-26 Published:2013-06-20

摘要/Abstract

摘要： 目的: 研究肾移植术后患者多药耐药相关蛋白(MRP2/ABCC2)基因多态性对环孢素(CsA)肝功能异常的影响。方法: 入选的339例肾移植受者均采用CsA治疗,检测患者rs717620(A/G)和rs2273697(G/A)多态性的基因型。此外,采用荧光偏振免疫法检测患者的CsA血药浓度,根据肾移植患者发生肝脏损伤的情况分为3组。结果: rs717620和rs2273697突变等位基因发生频率分别为 38.89%和 10.72%。ABCC2基因rs717620位点的G突变等位基因与CsA肝功能异常的发生密切相关,与对照组比较,CsA肝功异常组的GG基因型发生频率明显升高(P<0.05),AA基因型发生频率明显降低(P<0.05)。ABCC2基因rs2273697多态性与CsA肝功异常的发生无明显相关。基因型分析结果显示,这两个多态性对CsA谷浓度均无明显相关性,但rs2273697多态性对ALT和AST检测值有明显影响。对于ABCC2基因rs717620而言,GG基因型纯合子携带者的发病风险比AA型纯合子携带者高6倍(OR=6.960, 95%CI:1.636～29.610, P<0.01)。单倍体分析结果显示,与AA-AA基因型个体相比,GG-GG和GG-GA基因型个体移植术后发生CsA肝功异常的风险分别增加 5.909 倍和 13.333 倍。结论: ABCC2基因rs717620位点多态性与CsA肝功异常有明显相关性。ABCC2基因单倍体各基因型中,GG-GG和GG-GA单倍体基因型是肾移植术后发生CsA肝功异常的危险基因因素。

关键词: 环孢素, 肾移植受者, ABCC2基因, 肝功能

Abstract: AIM: To investigate the association between cyclosporine (CsA) induced liver disfunction and multidrug resistance-association protein 2 (MRP2/ABCC2) genetic polymorphisms in Chinese renal transplant recipients.METHODS: 339 renal allograft recipients were included in this study which were all treated by CsA. Two SNPs (rs717620 A/G; rs2273697 G/A) in chr.10 were genotyped. Besides, the CsA whole blood levels of renal transplant recipients were measured by fluorescence polarization immunoassay. All the subjects were divided into three groups according to the liver injury occurrence.RESULTS: The frequencies of rs717620 and rs2273697 mutation allele were 38.89% and 10.72%, respectively. The ABCC2 gene rs717620 SNP, G mutation allele was strongly associated with CsA induced liver disfunction. Compared with the control group, the distribution frequency of the GG genotype was significantly increased in CsA induced liver disfunction group (P<0.05), and that of the AA genotype was significantly increased (P<0.05). The ABCC2 gene rs2273697 polymorphism was not strongly associated with CsA hepatotoxicity. Genotype analysis revealed that there was no significant associations between these two SNPs and cyclosporine trough concentrations. But a positive association between rs2273697 polymorphism and ALT, AST concentrations was obse rved. The risk of disease for homozygous GG carriers was 6-fold higher (OR=6.960, 95%CI:1.636-29.610, P<0.01) in comparison with AA carriers in rs717620 gene. Analysis of haploid showed that compared with individuals carrying AA-AA, the risks of CsA induced liver disfunction after transplantation in the individuals carrying GG-GG and GG-GA were 5.909 and 13.333-fold higher, respectively.CONCLUSION: There is an association between the rs717620 genetic polymorphism in exon 1 of ABCC2 gene and CsA induced liver disfunction. The haploids carrying GG-GG and GG-GA have higher risk to result in CsA induced liver disfunction.

Key words: Cyclosporine, Renal transplant recipients, ABCC2 gene, Liver function

中图分类号:

R969

辛华雯, 刘慧明, 李元启, 黄晖, 赵丽, 余爱荣, 李罄, 吴笑春, 李维亮, 熊磊. ABCC2基因多态性与肾移植受者环孢素所致肝功能异常的相关性研究[J]. 中国临床药理学与治疗学, 2013, 18(7): 778-784.

XIN Hua-wen, LIU Hui-ming, LI Yuan-qi, HUANG Hui, ZHAO Li, YU Ai-rong, LI Qing, WU Xiao-chun, LI Wei-liang, XIONG Lei. Association of ABCC2 genetic polymorphism with liver disfunction induced by cyclosporine in Chinese renal transplant recipients[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(7): 778-784.

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