MDR1和CYP3A5基因多态性对环孢素血药浓度的影响

Effect of Polymorphisms in MDR1 and CYP3A5 on Blood Concentrations of Cyclosporine A in Aplastic Anemia Patients

关键词:  MDR1  CYP3A5  再生障碍性贫血  环孢素  血药浓度

Key words:  MDR1  CYP3A5  aplastic anemia  cyclosporine A  blood concentrations

摘要:

目的 研究MDR1基因和CYP3A5基因多态性与再生障碍性贫血患者环孢素药物浓度的关系。方法 在73例再生障碍性贫血(aplastic anemia，AA)患者中，采用基因测序法测定MDR1 G2677T/A基因型，RFLP法分析MDR1C1236T，MDR1 C3435T，CYP3A5*3基因型，并对这4个位点进行连锁分析。收集患者临床资料，对患者环孢素血药浓度进行检测分析。结果 本次研究的受试者中CYP3A5基因多态性仅发现*1*3和*3*3两种类型，且*3*3组的C0t显著高于*1*3组(P<0.05)。本次实验中患者MDR1基因中C1236T和C3435T两个SNP位点中各个基因型C_0t之间无显著性差异；而C2677T/A中突变纯合体(TT/TA)C_0t为(40±23.85)μg·kg·mL^-1·mg^-1与野生型(GG)(36.21±19.88)μg·kg·mL^-1·mg^-1相比有显著性增加。使用环孢素后不同单倍体型之间C_0t比较，各组之间都是TT-TT/A-TT>CT-GT/A-CT>CC-GG-CC。其中TT-TT/A-TT单倍体型组与CC-GG-CC单倍体型组相比具有显著性差异。结论 药物基因多态性研究对环孢素治疗再生障碍性贫血患者的临床合理用药有指导意义。

Abstract:

OBJECTIVE To determine the relationship between the Polymorphisms in MDR1 and CYP3A5 and the Blood Concentrations of Cyclosporine A in aplastic anemia patients. METHODS 73 aplastic anemia patients (AA) were genotyped on MDR1 G2677T/A using Gene sequencing method and MDR1C1236T, MDR1 C3435T, CYP3A5*3 using RFLP methods. The four SNPs were treated with linkage analysis. Clinical data and cyclosporine concentrations were collected and analyzed in relationship with genotyping results. RESULTS There were only two types of gene *1*3 and *3*3 found in this paper. The C_0t in *3*3 of group was higher than that in *1*3 group(P<0.05). There was no significant difference between the various genotypes of MDR1 C1236T and MDR1 C3435T in C_0t. The C_0t in C2677T/A(TT/TA) was (40±23.85)μg·kg·mL^-1·mg^-1 which was higher than the wild type(GG). Linkage analysis showed that 1236TT-2677TT/A-3435TT, 1236CT-2677GT/A-3435CT and 1236CC-2677GG-3435CC were closely linked. Moreover, in the form of haplotype, the trend of TT-TT/A-TT>CT-GT/A-CT> CC-GG-CC in blood levels was also observed. CONCLUSION There are some meaningfulness to rationalize the medication of cyclosporine A through the investigations of pharmacogenomics.