多药耐药基因MDR1C1236T多态性与炎症性肠病患者的活性代谢物6-TGNs的相关性

Relationship between MDR1C1236T polymorphism and active metabolite of 6-thioguanine nucleotide in patients with the inflammatory bowel disease

目的考察多药耐药基因MDR1的单核苷酸多态性(SNP)C1236T与炎症性肠病(IBD)患者服用硫嘌呤类药物后的活性代谢产物6-硫鸟苷酸(6-TGNs)的相关性。方法有105名患者纳入研究,收集全血提取DNA,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)法,进行MDR1C1236T基因型分析,采用HPLC方法检测红细胞内6-TGNs的浓度,并统计药物不良反应情况。卡方检验分析相关性。结果相同剂量下,6-TGNs浓度在1236CT/TT型携带者比CC型携带者高(P=0.048);同时,1236CT/TT型携带者服药后发生不良反应的风险显著高于1236CC型携带者(P=0.045)。结论 MDR1 1236 C>T突变与高6-TGNs浓度及高不良反应发生率密切相关。

Objective To investigate the relationship between multidrug resistance gene（MDR1） C1236T and 6-thioguanine nucleotide concentrations（6-TGNs） and thiopurine-induced adverse effects in patients with inflammatory bowel disease（IBD）.MethodsBlood samples and clinical data were collected from a cohort of 105 unrelated Chinese IBD patients who were receiving azathioprine（AZA）/6-mercaptopurine（6-MP） therapy.MDR1C1236T genotype was detected by polymerase chain reaction and restriction fragment length polymorphism（PCR-RFLP）,and erythrocyte 6-TGNs were determined by HPLC.The associations between MDR1 C1236T genotype and 6-TGNs level/adverse effects were evaluated using chi-square test.Results6-TGNs concentration was found higher in 1236 TT/CT carriers than that in 1236CC carriers treated with the same dose of AZA/6-MP（P=0.048）.Meanwhile,a positive correlation between 1236CT/TT and adverse effects was found in IBD patients（P=0.045）.ConclusionMDR1 1236 CT mutants play important role in higher 6-TGNs concentration and higher incidence of adverse reactions.