五个单核苷酸多态性在人类基因中的频率分布及其对中国儿童急性淋巴细胞白血病患者临床结局的影响。
Frequency distribution of five SNPs in human gene and their effects on clinical outcomes of Chinese pediatric patients with acute lymphoblastic leukemia.
机构信息
Department of Pediatrics, Beijing Shijitan Hospital, Capital Medical University, National Center for Children's Health, Beijing, China; Beijing Key Laboratory of Pediatric Hematology Oncology, National Center for Children's Health, Beijing, China; National Key Discipline of Pediatrics, Capital Medical University, National Center for Children's Health, Beijing, China; Key Laboratory of Major Diseases in Children, Ministry of Education, National Center for Children's Health, Beijing, China; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, National Center for Children's Health, Beijing, China; Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, National Center for Children's Health, Beijing, China; International Cooperation & Joint Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, National Center for Children's Health, Beijing, China;, Email:
出版信息
Pharmazie. 2020 Apr 6;75(4):142-146. doi: 10.1691/ph.2020.9932.
Methotrexate (MTX) is widely used in the treatment of childhood acute lymphoblastic leukemia (ALL). Gamma-glutamyl hydrolase (GGH) plays an important role in the disposition of MTX. The aim of this study was to investigate the frequency distribution of five SNPs in the human gene and their effects on serum MTX concentrations and clinical outcomes in Chinese children with ALL. Genotyping of 149 pediatric patients for rs11545078 C>T, rs11545077 G>A, rs1800909 T>C, rs11545076 T>G, and rs3758149 C>T was performed using the Sequenom MassARRAY system. Serum MTX concentrations were determined using a fluorescence polarization immunoassay. The five SNPs studied were in strong linkage. The minor allele frequencies for rs11545078, rs11545077, rs1800909, rs11545076, and rs3758149 were 5.3, 15.0, 14.3, 15.0, and 15.0%, respectively. Four haplotypes (CGTTC, CACGT, TACGT, and TATGT) were observed at frequencies of 84.9, 9.8, 4.5, and 0.8%, respectively. The median C/D ratios of serum MTX at 24 h and 42 h in children with variant haplotypes (12.30 and 0.08 μmol/L per g/m², respectively) were higher than those in wild haplotype carriers (11.85 and 0.07 μmol/L per g/m², respectively). The event-free survival of patients with variant haplotypes (89.2%) was significantly better than that of patients with wild haplotypes (71.9%, < 0.05). The relapse rate in children with variant haplotypes (8.1%) was lower than that in children with wild haplotypes (15.6%). These findings have implications for the efficacious use of MTX in childhood ALL patients.
甲氨蝶呤（MTX）广泛用于治疗儿童急性淋巴细胞白血病（ALL）。γ-谷氨酰水解酶（GGH）在 MTX 的处置中起重要作用。本研究旨在探讨中国人 ALL 患儿中基因的五个单核苷酸多态性（SNP）的频率分布及其对血清 MTX 浓度和临床结局的影响。采用Sequenom MassARRAY 系统对 149 例儿科患者的 rs11545078 C>T、rs11545077 G>A、rs1800909 T>C、rs11545076 T>G 和 rs3758149 C>T 进行基因分型。采用荧光偏振免疫测定法测定血清 MTX 浓度。所研究的五个 SNP 紧密连锁。rs11545078、rs11545077、rs1800909、rs11545076 和 rs3758149 的次要等位基因频率分别为 5.3%、15.0%、14.3%、15.0%和 15.0%。观察到四种单倍型（CGTTC、CACGT、TACGT 和 TATGT）的频率分别为 84.9%、9.8%、4.5%和 0.8%。变异单倍型患儿（12.30 和 0.08 μmol/L 每 g/m²，分别）24 小时和 42 小时血清 MTX 的 C/D 比值中位数高于野生型单倍型携带者（11.85 和 0.07 μmol/L 每 g/m²，分别）。变异单倍型患者的无事件生存（89.2%）明显优于野生型单倍型患者（71.9%，<0.05）。变异单倍型患儿（8.1%）的复发率低于野生型单倍型患儿（15.6%）。这些发现对儿童 ALL 患者有效使用 MTX 具有重要意义。
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