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目的探讨高脂血症患者CYP3A4*18A、*18B和MDR1 C3435T基因多态性对阿托伐他汀血药浓度、调脂疗效的影响。方法 115例福建籍汉族高脂血症患者以聚合酶链反应-限制性片段长度多态性法(polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)进行基因分型,HPLC-UV检测阿托伐他汀稳态血药谷浓度,均相酶法监测治疗前、用药1个月后血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、甘油三酯(TG)水平。用SPSS13.0软件以ANOVA方差分析高脂血症患者基因型与调脂疗效、血药浓度之间的关系。结果 115例高脂血症患者,CYP3A4*18A、*18B的突变频率分别为3.48%和23.48%,MDR1 C3435T突变率为31.74%,三基因位点SNPs分布与文献报道的国人正常人群无显著性差异(P>0.05);CYP3A4*18A和MDR1 C3435T各基因型患者ATV血药浓度组间及组内差异均无统计学意义(P>0.05)。CYP3A4*18B基因突变纯合子(AA)组患者ATV血药浓度显著高于突变杂合子(GA)组和野生型纯合子(GG)组(P=0.016)。CYP3A4*18A、MDR1 C3435T不同基因型患者的调脂效率无显著性差异(P>0.05),CYP3A4*18B基因的AA组患者TC调脂效果显著优于GA组和GG组患者(P=0.02);LDL-C变化率三基因型组间均有显著差异,依次为AA组>GA组>GG组(P=0.01),对TG和HDL-C的调节作用3种基因型患者无显著性差异(P>0.05)。治疗前后,TC的变化率与血药浓度呈显著性相关(P=0.031),而其余3种脂质变化率与血药浓度相关性无统计学意义(P>0.05)。结论 MDR1 C3435T与CYP3A4*18A基因SNPs(single nucleotide polymorphisms),不影响ATV血药浓度及其疗效。携带CYP3A4*18B基因的患者接受ATV治疗时,比未携带者血药浓度高,调脂疗效更显著。
Objective To investigate the effects of CYP3A4 * 18A, * 18B and MDR1 C3435T polymorphisms on atorvastatin plasma concentration and lipid-lowering efficacy in patients with hyperlipidemia. Methods One hundred and fifteen patients with Han-type hyperlipidemia in Fujian were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were measured at 1 month after treatment. , Triglyceride (TG) levels. SPSS 13.0 software ANOVA ANOVA analysis of patients with hyperlipidemia and lipid-lowering effect on the efficacy of the relationship between plasma concentrations. Results The mutation frequencies of CYP3A4 * 18A and * 18B were 3.48% and 23.48% in 115 patients with hyperlipidemia respectively, and the mutation rate of MDR1 C3435T was 31.74%. The distribution of SNPs in three gene loci was not significantly different from the normal people in China (P> 0.05). There was no significant difference in the concentration of ATV in CYP3A4 * 18A and MDR1 C3435T genotypes between the two groups (P> 0.05). The concentration of ATV in CYP3A4 * 18B mutation homozygous (AA) group was significantly higher than that in mutant heterozygous (GA) and wild type homozygote (P = 0.016). CYP3A4 * 18A, MDR1 C3435T patients with different genotypes of lipid regulation efficiency was no significant difference (P> 0.05), CYP3A4 * 18B gene AA group TC lipid control effect was significantly better than GA and GG patients (P = 0.02) (P = 0.01). There was no significant difference in the regulation of TG and HDL-C among the three genotypes in AA group> GA group> GG group (P> 0.05). Before and after treatment, the change rate of TC was significantly correlated with plasma concentration (P = 0.031), while there was no significant difference between the other three lipid changes and plasma concentration (P> 0.05). Conclusion The single nucleotide polymorphisms of MDR1 C3435T and CYP3A4 * 18A do not affect the concentration of ATV and its efficacy. Patients with CYP3A4 * 18B gene therapy at ATV, compared with non-carriers of high blood concentration, lipid-lowering effect is more significant.