MTRR基因多态性与颅内肿瘤患儿甲氨蝶呤血药浓度及不良反应的相关性研究  

Associations of MTRR gene polymorphism and methotrexate plasma concentration and adverse drug reaction in children with intracranial tumors

作　　者：赵丹琪 李苗[3] 时正媛 续茜桥 王淑梅 ZHAO Danqi;LI Miao;SHI Zhengyuan;XU Xiqiao;WANG Shumei(Dept.of Pharmacy,Beijing Shijitan Hospital,Capital Medical University,Beijing 100038,China;Dept.of Clinical Pharmacy,School of Pharmaceutical Sciences,Capital Medical University,Beijing 100069,China;Dept.of Pediatrics,Beijing Shijitan Hospital,Capital Medical University,Beijing 100038,China;Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use,Beijing 100038,China)

机构地区：[1]首都医科大学附属北京世纪坛医院药学部,北京100038 [2]首都医科大学药学院临床药学系,北京100069 [3]首都医科大学附属北京世纪坛医院儿科,北京100038 [4]临床合理用药生物特征谱学评价北京市重点实验室,北京100038

出　　处：《中国药房》2024年第21期2646-2651,共6页China Pharmacy

基　　金：国家自然科学基金项目(No.81872926);临床合理用药生物特征谱学评价北京市重点实验室项目(No.BZ0439);首都医科大学附属北京世纪坛医院科研基金项目(No.2023-c01);首都医科大学附属北京世纪坛医院青年基金项目(No.2022-q19)。

摘　　要：目的考察颅内肿瘤患儿甲硫氨酸合成酶还原酶(MTRR)rs10380 C>T基因多态性对甲氨蝶呤(MTX)血药浓度、不良反应和预后的影响。方法收集颅内肿瘤患儿的外周血,提取基因组DNA,用基质辅助激光解吸电离-飞行时间质谱法分析MTRR rs10380 C>T基因型,分析MTRR rs10380 C>T基因多态性与MTX血药浓度和剂量之间的比值(C/D比值)、不良反应、肿瘤复发和转移的相关性。基于生物信息学分析探索rs10380基因型与MTRR基因表达的关系及其可能机制。结果研究共纳入患儿75例,rs10380野生CC基因型和C等位基因的分布频率分别为62.67%和81.33%,变异CT基因型和T等位基因的分布频率分别为37.33%和18.67%,符合Hardy-Weinberg平衡(P>0.05)。CC基因型患儿的电解质紊乱发生率(51.06%)和肿瘤转移率(57.45%)显著高于CT基因型患儿(P<0.05)。两种基因型患儿的24 h和42 h C/D比值、复发率差异无统计学意义(P>0.05)。生信分析结果显示,MTRR蛋白主要与MMAA等10种蛋白协同发挥作用,并参与了含硫氨基酸生物合成等多种生物过程。结论MTRR rs10380 CC基因型可能是颅内肿瘤患儿MTX化疗后电解质紊乱和肿瘤转移的危险因素。OBJECTIVE To investigate the impact of the methionine synthase reductase(MTRR)rs10380 C>T gene polymorphism on methotrexate(MTX)plasma concentration,adverse drug reaction,and prognosis in children with intracranial tumors.METHODS Peripheral blood was collected from children with intracranial tumors,and genomic DNA was extracted.The MTRR rs10380 C>T genotype was analyzed using matrix-assisted laser desorption/ionization-time of flight-mass spectrometry.The association of the MTRR rs10380 C>T gene polymorphism with the ratio of MTX plasma concentration to dose(C/D ratio),adverse drug reaction,tumor recurrence,and metastasis was analyzed.Bioinformatics analysis was used to explore the association of the rs10380 genotype and MTRR gene expression and its possible mechanisms.RESULTS A total of 75 children were included in the study.The distribution frequencies of the wild-type CC genotype and C allele of rs10380 were 62.67%and 81.33%,respectively,while the distribution frequencies of the variant CT genotype and T allele were 37.33%and 18.67%,respectively,which were in accordance with Hardy-Weinberg equilibrium(P>0.05).The incidence of electrolyte disorders(51.06%)and tumor metastasis rate(57.45%)in children with the CC genotype were significantly higher than those with the CT genotype(P<0.05).No significant differences were observed in the 24-hour and 42-hour C/D ratios and recurrence rates between the two genotypes of children(P>0.05).Bioinformatics analysis showed that MTRR protein mainly works in conjunction with 10 proteins,including MMAA,and was involved in various biological processes such as sulfur amino acid biosynthesis.CONCLUSIONS The MTRR rs10380 CC genotype may be a risk factor for electrolyte disorders and tumor metastasis in children with intracranial tumors after MTX chemotherapy.

关 键 词：颅内肿瘤 甲氨蝶呤 甲硫氨酸合成酶还原酶 基因多态性 不良反应 预后 

分 类 号：R969[医药卫生—药理学]