MTRR和SLCO1B1基因多态性与ALL患儿MTX血药浓度及HD-MTX致不良反应的相关性研究
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篇名: MTRR和SLCO1B1基因多态性与ALL患儿MTX血药浓度及HD-MTX致不良反应的相关性研究
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摘要: 目的:研究MTRR基因rs1801394位点、SLCO1B1基因rs11045879位点多态性与急性淋巴细胞白血病(ALL)患儿甲氨蝶呤(MTX)血药浓度及大剂量甲氨蝶呤(HD-MTX)致不良反应的相关性。方法:回顾性收集2015年10月-2018年9月四川省人民医院收治的接受HD-MTX治疗且处于巩固化疗期的四川地区汉族ALL住院患儿70例,采用均相酶扩大免疫法检测患儿给药后48、72 h时的血药浓度,采用实时荧光定量聚合酶链反应法检测其基因分型;分析MTRR、SLCO1B1基因多态性与MTX血药浓度[剂量校正浓度(c48 h/D,48 h)、不同血药浓度范围(≤0.1、>0.1 μmol/L)患儿比例(72 h)]及不良反应(骨髓抑制、肝功能损害、胃肠道反应、黏膜损伤、皮疹等)的相关性;采用Wald渐进法对不同影响因素(基因多态性、MTX血药浓度、免疫分型、体质量指数等)与不良反应的相关性进行二元Logistic回归分析。结果:共检出MTRR基因AA、AG、GG型患儿31、32、7例,SLCO1B1基因TT、TC、CC型患儿23、37、10例,各基因型频率均符合Hardy-Weinberg平衡(P>0.05)。MTRR和SLCO1B1各基因型患儿c48 h/D(48 h)以及不同血药浓度范围患儿比例(72 h)比较差异均无统计学意义(P>0.05)。MTRR各基因型患儿肝功能损害发生率差异显著(P<0.05),且AA型显著高于AG+GG型(P<0.05);而MTRR基因多态性与其他不良反应发生率,SLCO1B1基因多态性与各不良反应发生率均不相关(P>0.05)。二元Logistic回归分析结果显示,ALL患儿肝功能损害与MTRR基因多态性相关,胃肠道反应与72 h血药浓度>0.1 μmol/L与否相关,黏膜损伤与患儿免疫分型和体质量指数相关,皮疹与患儿体质量相关(P<0.05)。结论:MTRR基因rs1801394位点多态性可能与ALL患儿HD-MTX致肝功能损害的发生相关,但该多态性和SLCO1B1基因rs11045879位点多态性均与患儿体内MTX的血药浓度无关。
ABSTRACT: OBJECTIVE: To study the relationships of polymorphism of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus with drug concentration of methotrexate (MTX) and high-dose MTX (HD-MTX)-induced ADR in acute lymphoblastic leukemia (ALL) children. METHODS: From Oct. 2015 to Sept. 2018, 70 ALL hospitalized children of Han nationality in Sichuan area who received HD-MTX treatment and were in consolidation chemotherapy were selected retrospectively from Sichuan People’s Hospital. The blood concentration of MTX at 48 and 72 hours after administration was measured by EMIT. The genetic typing of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus were detected with real-time PCR. The relationships of the polymorphism of MTRR gene and SLCO1B1 gene with MTX blood concentration [dose-corrected concentration (c48 h/D,48 h), the proportion of children with different concentration of MTX (≤0.1, >0.1 μmol/L)] and ADR (such as myelosuppression, liver function damage, gastrointestinal response, mucosal damage, rash, etc.) were analyzed. Binary Logistic regression analysis for the correlation of ADR with different influencing factors (gene polymor- phism, blood concentration of MTX, immunophenotyping, body mass index, etc.) was carried out by Wald method. RESULTS: Totally 31, 32, 7 children with MTRR gene AA, AG and GG genotype, while 23, 37, 10 children with SLCO1B1 gene TT, TC and CC genotype were detected. The distribution of each genotype in 70 children conformed to Hardy-Weinberg equilibrium (P>0.05). There was no significant difference in c48 h/D(48 h) of children and the proportion of children with different concentration of MTX (72 h) among difterent genotypes of MTRR and SLCO1B1 gene (P>0.05). There was statistical significance in the incidence of liver function injury in children with different genotypes of MTRR gene (P<0.05), and the AA genotype was significantly higher than the AG+GG genotype (P<0.05). There was no correlation of MTRR gene polymorphism with the incidence of other ADR, neither SLCO1B1 gene polymorphism with the incidence of ADR (P>0.05). The results of Binary Logistic regression analysis showed that liver function damage in ALL children was related to the gene polymorphism of MTRR; gastrointestinal reaction was related to whether the plasma concentration was more than 0.1 μmol/L at 72 h; mucosal damage was related to the immune type and BMI of children; the occurrence of skin allergy was correlated with body weight of children(P<0.05). CONCLUSIONS: Gene polymorphism of MTRR rs1801394 locus may associated with the occurrence of HD-HTX-induced liver function injury in ALL children, but its polymorphism and gene polymorphism of SLCO1B1 rs11045879 locus are not related to MTX blood concentration in ALL children.
期刊: 2019年第30卷第24期
作者: 何霞,姚平立,吴宇,侯正尧,李星星,陈璐,张丽娟,杨思芸,肖洪涛,童荣生
AUTHORS: HE Xia,YAO Pingli,WU Yu,HOU Zhengyao,LI Xingxing,CHEN Lu,ZHANG Lijuan,YANG Siyun,XIAO Hongtao,TONG Rongsheng
关键字: 急性淋巴细胞白血病;儿童;MTRR基因;SLCO1B1基因;单核苷酸多态性;甲氨蝶呤;血药浓度;不良反应
KEYWORDS: Acute lymphoblastic leukemia; Children; MTRR gene; SLCO1B1 gene; Single nucleotide polymorphism; Methotrexate; Blood concentration; ADR
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