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目的探讨尿苷二磷酸葡糖醛酸基转移酶1家族肽A(UGT1A)基因多态性与抗肿瘤药伊立替康所致不良反应的相关性,为肿瘤患者个体化用药提供参考。方法研究对象为233名健康志愿者和196例应用伊立替康治疗的肿瘤患者。健康志愿者中男性169名,女性64名;平均年龄(25±5)岁。肿瘤患者中肠癌92例,宫颈癌45例,卵巢上皮细胞癌59例;男性54例,女性142例;平均年龄(61±19)岁。采用焦磷酸测序法对2组受试者进行UGT1A1*6、UGT1A1*28、UGT1A3*1、UGT1A3*2、UGT1A3*3、UGT1A3*4和UGT1A9*22基因多态性检测,比较2组受试者UGT1A基因型突变频率,比较不同UGT1A基因型患者迟发性腹泻和白细胞和/或中性粒细胞减少发生率,采用Logistic回归方法分析伊立替康致不良反应的危险因素,结果以相对危险度(OR)及95%置信区间表示。结果肿瘤患者UGT1A3*2基因型突变频率明显低于健康志愿者(50.3%比68.5%,P=0.014),而UGT1A3*3基因型突变频率明显高于健康志愿者(26.0%比6.2%,P=0.001)。196例肿瘤患者Ⅱ~Ⅳ度迟发性腹泻发生率为48.5%(95例),Ⅲ~Ⅳ度迟发性腹泻发生率为11.2%(22例);Ⅲ~Ⅳ度中性粒细胞减少发生率为49.0%(96例)。UGT1A1*28位点野生型纯合子(WW)基因型携带者Ⅱ~Ⅳ度和Ⅲ~Ⅳ度迟发性腹泻发生率均明显低于突变型杂合子(WM)+突变型纯合子(MM)基因型携带者[Ⅱ~Ⅳ度:40.4%(57/141)比69.1%(38/55),P=0.006;Ⅲ~Ⅳ度:5.7%(8/141)比25.5%(14/55),P=0.001];UGT1A9*22位点WW基因型携带者Ⅱ~Ⅳ度迟发型腹泻发生率明显低于WM+MM基因型携带者[26.2%(17/65)比47.6%(40/84),P=0.006;26.2%(17/65)比51.1%(24/47),P=0.0057],未发现不同基因型患者之间Ⅲ~Ⅳ度中性粒细胞减少发生率差异存在统计学意义。Logistic回归分析显示UGT1A基因型与迟发性腹泻的发生相关(OR=5.657,95%置信区间为4.782~7.245,P=0.039)。结论 UGT1A1*28和UGT1A9*22基因多态性可增加伊立替康所致迟发性腹泻的风险。
Objective To investigate the association of uridine diphosphate glucuronyltransferase 1 family peptide A (UGT1A) gene polymorphism with the adverse reaction induced by irinotecan in antitumor drug, and to provide a reference for the individualized drug use of cancer patients. METHODS: A total of 233 healthy volunteers and 196 cancer patients treated with irinotecan were enrolled. There were 169 males and 64 females in healthy volunteers, with an average age of 25 ± 5 years. There were 92 cases of colorectal cancer, 45 cases of cervical cancer and 59 cases of epithelial ovarian cancer. There were 54 males and 142 females with a mean age of (61 ± 19) years. The polymorphisms of UGT1A1 * 6, UGT1A1 * 28, UGT1A3 * 1, UGT1A3 * 2, UGT1A3 * 3, UGT1A3 * 4 and UGT1A9 * 22 were detected by pyrosequencing in two groups. UGT1A genotype frequency of mutations in patients with different genotype UGT1A delayed diarrhea and leucocyte and / or neutropenia incidence, the use of Logistic regression analysis of irinotecan-induced adverse reaction risk factors, the results of relative risk (OR) and 95% confidence interval. Results The mutation frequency of UGT1A3 * 2 genotype in cancer patients was significantly lower than that in healthy volunteers (50.3% vs 68.5%, P = 0.014), while the mutation frequency of UGT1A3 * 3 genotype was significantly higher than that in healthy volunteers (26.0% vs. 6.2%, P = 0.001). The incidence of late-onset diarrhea in grade Ⅱ-Ⅳ of 196 patients was 48.5% (95 cases), and the incidence of late-onset diarrhea of grade Ⅲ-Ⅳ was 11.2% (n = 22). Neutropenia The rate was 49.0% (96 cases). The incidence of Ⅱ ~ Ⅳ and Ⅲ ~ Ⅳ delayed diarrhea in wild type homozygote (WW) genotype of UGT1A1 * 28 locus were significantly lower than that of mutant heterozygous (WM) + mutant homozygote (MM) (P = 0.006); Ⅲ ~ Ⅳ degrees: 5.7% (8/141) vs 25.5% (14/55) in patients with genotype carriers [Ⅱ ~ Ⅳ degrees: 40.4% (57/141) , P = 0.001]. The incidence of delayed secondary diarrhea with Ⅱ ~ Ⅳ degree in UGT1A9 * 22 locus was significantly lower than that in WM + MM carriers [26.2% (17/65) vs 47.6% (40/84) ), P = 0.006; 26.2% (17/65) vs 51.1% (24/47), P = 0.0057]. There was no statistical difference in the incidence of grade Ⅲ ~ Ⅳ neutropenia among different genotypes significance. Logistic regression analysis showed that UGT1A genotype was associated with the occurrence of delayed diarrhea (OR = 5.657, 95% confidence interval 4.782-7.245, P = 0.039). Conclusion The polymorphisms of UGT1A1 * 28 and UGT1A9 * 22 may increase the risk of delayed diarrhea caused by irinotecan.