ABCB12677G>T/A基因多态性与自身免疫病患者环孢素A血药浓度个体差异的相关性研究

Correlationship between ATP binding cassette subfamily B member 12677G>T/A gene polymorphism and cyclosporine blood concentration in patients with autoimmune diseases

目的测定自身免疫病患者的全血环孢素A(CsA)药物浓度,并对可能影响环孢素A血药浓度的代谢酶、转运体和作用靶点的基因多态性等因素进行分析。方法采用酶放大免疫测定法检测193例自身免疫病患者环孢素A稳态血药谷浓度(CsA C_(0)),并检测入组患者的基因型:CYP3A420230C>T、CYP3A56986A>G、ABCB11236C>T、ABCB12677G>T/A、ABCB13435C>T、POR 1508C>T及FPR1 C>G。采用单因素方差分析,LSD-t检验及χ^(2)检验上述位点的基因多态性对环孢素A血药浓度的影响。结果193例自身免疫病患者服用环孢素A剂量为75~200 mg/d,患者的血药浓度分布为33.0~313.8 ng/ml。服药日剂量(χ^(2)=21.908,P=0.001)和年龄(F=4.262,P=0.006)对患者环孢素A血药浓度的影响差异有统计学意义。ABCB12677G>T/A(rs2032582)基因多态性对单位剂量CsA C_(0)(CsA C_(0)/d)有影响,野生型(GG)患者的CsA C_(0)/d[(0.81±0.42)ng·ml^(-1)·mg^(-1)]较杂合突变型[GT/GA,(0.65±0.30)ng·ml^(-1)·mg^(-1),P=0.023]和纯合突变型[TT/AA/TA(0.66±0.34)ng·ml^(-1)·mg^(-1),P=0.039]显著升高。结论环孢素A血药浓度在个体间差异大,ABCB12677G>T/A基因的野生型患者环孢素A血药浓度的C_(0)/d显著高于突变型患者。

Objective To investigate the distribution of blood concentration of cyclosporine(CsA)in patients with autoimmune disease in China,and analyze the effect of genetic polymorphisms of CsA-metabolizing enzymes,transporters and target enzymes on CsA levels.Methods Steady-state trough blood concentrations(CsA C_(0))of 193 patients'were detected by enzyme multiplied immunoassay technique.The genotype of the following sites in the included patients were sequenced by reverse transcription-polymerase chain reaction(RT-PCR):cytochrome P450(CYP)3A420230C>T,CYP3A56986A>G,ATP binding cassette subfamily B member 1(ABCB1)1236C>T,ABCB12677G>T/A,ABCB13435C>T,cytochrome P450 oxidoreductase(POR)1508 C>T and formyl peptide receptor 1(FPR1)C>G were sequenced by RT-PCR.The influence of the gene polymorphism of the above-mentioned sites on the blood concentration of CsA was analyzed by using One-way analysis of variance(ANOVA),LSD-t test,Chi-square test.Results One hundred and ninety-three patients included took CsA.The doses ranged from 75-200 mg/d and the patients'blood concentration distribution span was wide(33.0-313.8 ng/ml).The daily dose(χ^(2)=21.908,P=0.001)and age(F=4.262,P=0.006)had significant effect on the plasma concentration of CsA.ABCB12677G>T/A(rs2032582)gene polymorphism impacted on the unit dose of CsA C_(0)(CsA C_(0)/d),CsA C_(0)/d[(0.81±0.42)ng·ml^(-1)·mg^(-1)]in wild type(GG)was higher than heterozygous mutant[GT/GA,(0.65±0.30)ng·ml^(-1)·mg^(-1)],P=0.023)and homozygous mutant(TT/AA/TA,(0.66±0.34)ng·ml^(-1)·mg^(-1),P=0.039).Conclusion The blood concentration of patients varies greatly among individuals.The Cold of CsA in wild type patients with ABCB12677G>T/A gene is signifficantly higher than that in mutant patients.