IMPDH1基因多态性与肾移植患者麦考酚酸类药物药效学的相关性分析
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摘要
探讨IMPDH1基因多态性对肾移植患者麦考酚酸类药物药效学的影响。纳入315例肾移植术后进行三联免疫疗法(麦考酚酸类药物+他克莫司+泼尼松)的患者。采用Agena Mass ARRAY?方法检测患者IMPDH1基因型。通过高效液相色谱法检测术后稳定期患者麦考酚酸(MPA)及其主要代谢物麦考酚酸葡萄糖苷酸(MPAG)的血浆药物浓度。应用SPSS 21.0软件对IMPDH1基因多态性(rs10954183、rs12536006、rs13242340、rs2278293、rs2288549)与肾移植患者排斥、术后感染等指标的相关性进行分析。结果显示,IMPDH1 rs2288549 AG型是肾移植患者术后出现急性排斥反应的危险因素(OR=6.629,P<0.05);IMPDH1 rs2278293 CT型是肾移植患者术后出现感染的危险因素(OR=2.812,P<0.05)。以上研究表明,IMPDH1 rs2288549是肾移植患者术后出现急性排斥反应的影响因素,IMPDH1 rs2278293是肾移植患者术后出现感染的影响因素,上述SNP可作为参考优化临床用药方案,提高疗效,降低不良反应的发生率。
The study was designed to investigate the effect of IMPDH1 gene polymorphism on the pharmacodynamics of mycophenolic acid in the renal transplant patients. 315 patients with renal transplantation were treated with triple immunotherapy(mycophenolic acid + tacrolimus + prednisone). The Agena Mass ARRAY assay was used to detect the IMPDH1 genotypes in patients above. The plasma drug concentration of mycophenolic acid(MPA) and its main metabolite mycophenolic acid glucuronide(MPAG) was detected by high performance liquid chromatography(HPLC). The correlation between IMPDH1 gene polymorphism(rs10954183, rs12536006, rs13242340, rs2278293, rs2288549) and rejection and postoperative infection in renal transplant recipients were analyzed by SPSS 21 software. The result showed that IMPDH1 rs2288549 GG is a risk factor for acute rejection after renal transplantation(P < 0.05), and IMPDH1 rs2278293 CT is a risk factor for infection after renal transplantation(P < 0.05). Above all, IMPDH1 rs2288549 is an important factor of acute rejection after renal transplantation, IMPDH1 rs2278293 is an important factor affecting the emergence of infection after renal transplantation. The SNPs may help to optimize clinical medication to reduce the incidence of adverse reaction.
The study was designed to investigate the effect of IMPDH1 gene polymorphism on the pharmacodynamics of mycophenolic acid in the renal transplant patients. 315 patients with renal transplantation were treated with triple immunotherapy(mycophenolic acid + tacrolimus + prednisone). The Agena Mass ARRAY assay was used to detect the IMPDH1 genotypes in patients above. The plasma drug concentration of mycophenolic acid(MPA) and its main metabolite mycophenolic acid glucuronide(MPAG) was detected by high performance liquid chromatography(HPLC). The correlation between IMPDH1 gene polymorphism(rs10954183, rs12536006, rs13242340, rs2278293, rs2288549) and rejection and postoperative infection in renal transplant recipients were analyzed by SPSS 21 software. The result showed that IMPDH1 rs2288549 GG is a risk factor for acute rejection after renal transplantation(P < 0.05), and IMPDH1 rs2278293 CT is a risk factor for infection after renal transplantation(P < 0.05). Above all, IMPDH1 rs2288549 is an important factor of acute rejection after renal transplantation, IMPDH1 rs2278293 is an important factor affecting the emergence of infection after renal transplantation. The SNPs may help to optimize clinical medication to reduce the incidence of adverse reaction.
引文
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[7]Wang J,Yang JW,Zeevi A,et al.IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients[J].Clin Pharmacol Ther,2008,83:711-717.
[8]Kagaya H,Miura M,Saito M,et al.Correlation of IMPDH1gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation[J].Basic Clin Pharmacol Toxicol,2010,107:631-636.
[9]Zukowska A,Kotfis K,Kaczmarczyk M,et al.Impact of graft infection on long-term survival after kidney transplant[J].Transplant Proc,2014,46:2752-2754.
[10]Picard N,Marquet P.The influence of pharmacogenetics and cofactors on clinical outcomes in kidney transplantation[J].Expert Opin Drug Metab Toxicol,2011,7:731-743.
[11]Hronova K,Sima M,Svetlik S,et al.Pharmacogenetics and immunosuppressive drugs[J].Expert Rev Clin Pharmacol,2014,7:821-835.
[2]Qi L,Li JL,Liu XM,et al.Associations of VDR polymorphisms with tacrolimus concentrations in Chinese renal transplant recipients[J].Acta Pharm Sin(药学学报),2017,52:760-765.
[3]Ren B,He QY,Xu Q,et al.Prediction of mycophenolic acid exposure in renal transplantation recipients by artificial neural network[J].Acta Pharm Sin(药学学报),2009,44:1397-1401.
[4]Huang JW.The Dssociation of Dosage Form and Pharmacogenetic Factors with Drug Exposure and Adverse Reaction of Mycophenolic Acid in Renal Transplant Recipients(剂型和药动学遗传因素与肾移植患者霉酚酸暴露量及不良反应相关性研究)[D].Guangzhou:Sun Yat-sen University,2011.
[5]Loparev VN,Cartas MA,Monken CE,et al.An efficient and simple method of DNA extraction from whole blood and cell lines to identify infectious agents[J].J Virol Methods,1991,34:105-112.
[6]Cao W,Xiao H,Lai X,et al.Genetic variations in the mycophenolate mofetil target enzyme are associated with acute GVHD risk after related and unrelated hematopoietic cell transplantation[J].Biol Blood Marrow Transplant,2012,18:273-279.
[7]Wang J,Yang JW,Zeevi A,et al.IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients[J].Clin Pharmacol Ther,2008,83:711-717.
[8]Kagaya H,Miura M,Saito M,et al.Correlation of IMPDH1gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation[J].Basic Clin Pharmacol Toxicol,2010,107:631-636.
[9]Zukowska A,Kotfis K,Kaczmarczyk M,et al.Impact of graft infection on long-term survival after kidney transplant[J].Transplant Proc,2014,46:2752-2754.
[10]Picard N,Marquet P.The influence of pharmacogenetics and cofactors on clinical outcomes in kidney transplantation[J].Expert Opin Drug Metab Toxicol,2011,7:731-743.
[11]Hronova K,Sima M,Svetlik S,et al.Pharmacogenetics and immunosuppressive drugs[J].Expert Rev Clin Pharmacol,2014,7:821-835.