Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, People's Republic of China.
J Transl Med. 2018 Jul 17;16(1):197. doi: 10.1186/s12967-018-1579-3.
UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver.
UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated.
After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A16 (77.0%) or the UGT1A128 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 × 10) and better overall survival (HR = 0.787, 95% CI 0.627-0.990, P = 0.040) as compared with homozygotes for both polymorphisms.
Our results suggest that UGT1A128 and UGT1A16 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.
UDP-葡糖醛酸基转移酶 1A 亚家族（UGT1A）酶可以通过葡糖醛酸化使阿糖胞苷（Ara-C）失活，因此作为 Ara-C 反应个体差异的候选基因。UGT1A1 是在人类肝脏中表达的主要 UGT1A 同工酶。
在 726 例接受基于 Ara-C 的方案治疗的成人急性髓系白血病（AML）患者中，对导致 UGT1A1 活性降低的 UGT1A16 和28 多态性进行了基因分型。评估了这两种多态性对患者化疗敏感性和疾病预后的影响。
在接受一个或两个疗程基于 Ara-C 的诱导化疗后，携带 UGT1A16（77.0%）或 UGT1A128（76.4%）等位基因的患者完全缓解（CR）率明显高于相应的野生型纯合子（分别为 66.9%和 68.5%）。携带 UGT1A16 或28 等位基因的患者发生非 CR 的风险明显降低（OR=0.528，95%CI 0.379-0.737，P=1.7×10），总生存（HR=0.787，95%CI 0.627-0.990，P=0.040）明显优于两种多态性的纯合子。
我们的结果表明，在中国接受 Ara-C 治疗的 AML 患者中，UGT1A128 和 UGT1A16 与改善的临床结局相关。
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