Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity
Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity
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DOI：
10.1097/01213011-200501000-00006
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发表时间：
2005-01
影响因子：
2.6
通讯作者：
C. Kitagawa;M. Ando;Y. Ando;Y. Sekido;K. Wakai;K. Imaizumi;K. Shimokata;Y. Hasegawa
中科院分区：
文献类型：
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作者：
C. Kitagawa;M. Ando;Y. Ando;Y. Sekido;K. Wakai;K. Imaizumi;K. Shimokata;Y. Hasegawa
UDP-葡萄糖醛酸基转移酶（UGT）1A 1基因的遗传多态性与伊立替康活性代谢产物SN-38的葡萄糖醛酸化活性降低相关，UGT 1A 1 *28已被证明是伊立替康毒性的预测因素。据报道，UGT 1A 1启动子区域的苯巴比妥响应增强子模块（PBREM）与该基因的转录活性相关。我们研究了PBREM（T-3279 G）多态性是否会影响患者间对伊立替康毒性敏感性的差异。研究人群包括119例接受伊立替康治疗的癌症患者。我们回顾了他们的临床记录，包括患者特征，并观察了伊立替康输注后的毒性水平。通过测序分析进行基因分型。进行逻辑回归分析以评估基因型与伊立替康毒性之间的关系。我们在68例患者中鉴定了T-3279 G参考等位基因的纯合子，37例患者中鉴定了杂合子，14例患者中鉴定了变异体的纯合子。Logistic回归分析表明T-3279 G纯合子与严重毒性之间存在显著相关性（比值比5.80; 95%置信区间1.67-20.1）。然而，多变量分析，包括UGT 1A 1 *28多态性的数据，揭示了减少的关联，由于这些多态性之间的高度显着的连锁不平衡。我们的研究结果表明，T-3279 G和UGT 1A 1 *28多态性之间存在高度显着的连锁不平衡，并且T-3279 G和UGT 1A 1 *28的变体协同降低UGT 1A 1启动子的转录活性。T-3279 G和UGT 1A 1 *28基因型的测定可能在预测癌症患者中的严重伊立替康毒性方面具有临床意义。
Genetic polymorphism of the UDP-glucuronosyltransferase (UGT) 1A1 gene is associated with the decreased glucuronidation activity of an active metabolite of irinotecan, SN-38, and UGT1A1*28 has been shown as a predictive factor for irinotecan toxicity. The phenobarbital-responsive enhancer module (PBREM) of the UGT1A1 promoter region has been reportedly associated with the transcriptional activity of the gene. We investigated whether the polymorphism of PBREM (T-3279G) would affect inter-patient variations in sensitivity to irinotecan toxicity. The study population comprised 119 cancer patients who had received irinotecan. We reviewed their clinical records, including patient characteristics, and observed their toxicity levels following irinotecan infusion. Genotyping was performed by sequencing analyses. Logistic regression analyses were performed to assess the relationship between genotypes and irinotecan toxicity. We identified the homozygotes of the reference allele for T-3279G in 68 patients, the heterozygotes in 37, and the homozygotes for the variant in 14. Logistic regression analysis indicated a significant association between the homozygotes for T-3279G and the severe toxicity (odds ratio 5.80; 95% confidence interval 1.67–20.1). However, multivariate analysis, including the data of UGT1A1*28 polymorphism, revealed a diminution of the association due to a highly significant linkage disequilibrium between these polymorphisms. Our results suggest that a highly significant linkage disequilibrium exists between T-3279G and UGT1A1*28 polymorphisms, and that the variants of T-3279G and UGT1A1*28 cooperatively decrease transcriptional activity of the UGT1A1 promoter. The determination of T-3279G and UGT1A1*28 genotypes might be clinically useful in predicting severe irinotecan toxicity in cancer patients.