目的 Meta分析探讨NUDT15 c.415C>T位点单核苷酸多态性(SNP)与巯嘌呤类药物所致患者白细胞减少的相关性。方法检索Pubmed、EMbase、中国知网、万方数据库等数据库,同时利用计算机检索、文献追溯等途径收集国内外公开发表的关于NUDT1...目的 Meta分析探讨NUDT15 c.415C>T位点单核苷酸多态性(SNP)与巯嘌呤类药物所致患者白细胞减少的相关性。方法检索Pubmed、EMbase、中国知网、万方数据库等数据库,同时利用计算机检索、文献追溯等途径收集国内外公开发表的关于NUDT15与巯嘌呤类药物所致白细胞减少的相关性研究文献。检索的文献为截止到2018年2月28日已发表的所有文献。采用NOS标准评价纳入各个原始文献的质量。采用OR值和95%置信区间(CI)来评价NUDT15 c.415C> T和白细胞减少之间的关系。结果纳入7篇研究,共有1 198个接受巯嘌呤类药物治疗的患者。Meta分析结果如下:显性遗传模型(CT+TT vs CC,OR=9.29,95%CI:6.43～13.44,P=0.0001),纯合子模型(TT vs CC,OR=37.32,95%CI:14.199～98.10,P=0.0009),杂合子模型(CT vs CC,OR=7.42,95%CI:5.05～10.88,P=0.0005),隐性遗传模型(TT vs CT,OR=8.79,95%CI:3.497～22.12)。按所有纳入研究的对象Meta分析结果显示,携带T等位基因的NUDT15 c.415C> T与巯嘌呤所导致的白细胞减少的发生具有强相关性(P<0.05)。结论对于巯嘌呤来说,在亚洲人口中,NUDT15 c.415C> T可能是一个高度可信的药物基因预测者。由于该研究纳入的文献数量较少,相关结果需要更多研究予以验证。展开更多
AIM To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine(AZA)-induced leukopenia in inflammatory bowel disease(IBD).METHODS This study enrolled 219 patients diagnosed w...AIM To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine(AZA)-induced leukopenia in inflammatory bowel disease(IBD).METHODS This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.RESULTS There were 219 patients with IBD(160 men and 59 women), including 39 who were confirmed with ulcerative colitis(UC), 176 with Crohn's disease(CD) and 4 with undetermined IBD(UIBD). There were 44 patients(20.1%) with mutant genotype of NUDT15(C/T); among them, 16 received AZA, and 8(50%) developed leukopenia. There were 175 patients(79.7%) with wild genotype of NUDT15(C/C); among them, 64 received AZA, and 11(17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C(P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G(1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients(98.6%) were found to bear the wild genotype of TPMT(A/A); among them, 79 patients received AZA, and 18(22.8%) developed leukopenia, and there was no significant difference from those with A/G(P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1%(P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.CONCLUSION Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.展开更多
AIM The single nucleotide polymorphism(SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn's disease. Meanwhile, three additional genetic variants of NUDT15 were...AIM The single nucleotide polymorphism(SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn's disease. Meanwhile, three additional genetic variants of NUDT15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of NUDT15 in patients with inflammatory bowel disease(IBD) treated with thiopurines.METHODS Ninety-six Japanese patients with IBD were enrolled. Genotyping for the NUDT15 and TPMT genes was performed using Custom Taq Man SNP genotyping assays or Sanger sequencing. The changes in white blood cell(WBC) count, mean corpuscular volume(MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR were evaluated.RESULTS Genetic variants of exon 1 and exon 3 of NUDT15 were identified in 24 of 96 patients(25.0%). C.52G > A and c.36_37 insG GAGTC in exon 1 were found in three patients each. All three patients with c.36_37 insG GAGTC in exon 1 were heterozygotes of p.Arg139 Cys in exon 3. Eighteen patients had p.Arg139 Cys in exon 3 alone. The WBC count gradually decreased after initiation of thiopurine treatment in the mutated cases(n = 24), and was significantly lower at 6, 8, 10, and 16 wk(P = 0.0271, 0.0037, 0.0051, and 0.0185, respectively). The WBC counts were also evaluated in patients with and without prednisolone treatment. In the patients with prednisolone treatment, the WBC count tended to show a greater decrease in the mutated cases, with significant differences at 8 and 10 wk(P = 0.012 and 0.029, respectively). In the patients without prednisolone treatment, the WBC count was significantly lower at 2, 4, 8, and 14 wk in mutated cases(P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine treatment in the mutated cases, and was significantly higher at 10 wk(P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR did not differ significantly between the wildtype and mutated cases. TPMT mutations were not found in any of the patients.CONCLUSION Mutations in exon 1 of NUDT15 also affect thiopurineinduced leukopenia in patients with IBD. To discuss thiopurine-induced leukopenia in more detail, investigation of SNPs in both exon 1 and exon 3 of NUDT15 is needed.展开更多
目的:系统评价rs116855232与6-巯基嘌呤(6-MP)治疗儿童急性淋巴细胞白血病(ALL)的安全性,旨为临床治疗提供循证医学证据。方法:系统检索PubMed、Web of Science、CNKI和万方数据库,收集有关rs116855232位点多态性与6-MP所致ALL白细胞减...目的:系统评价rs116855232与6-巯基嘌呤(6-MP)治疗儿童急性淋巴细胞白血病(ALL)的安全性,旨为临床治疗提供循证医学证据。方法:系统检索PubMed、Web of Science、CNKI和万方数据库,收集有关rs116855232位点多态性与6-MP所致ALL白细胞减少的临床相关研究,利用Stata软件对纳入文献进行Meta分析,计算合并OR值及95%CI。结果:共纳入5项病例对照研究,Meta分析显示rs116855232位点多态性与6-MP所致患者白细胞减少显著相关(P<0.05),其中显性模型(OR=8.06,95%CI:3.40–19.07),纯合子模型(OR=8.20,95%CI:3.14–21.36)以及杂合子模型(OR=7.62,95%CI:1.45–39.98)可以显著增加治疗过程中白细胞减少的风险。然而隐性模型与白细胞减少之间则未发现显著相关性(OR=5.13,95%CI:0.99–26.58);除此之外,我们发现rs116855232可以显著增加患儿早期治疗过程中白细胞计数低于2×10~9的发生率(P<0.05)。结论:NUDT15单核苷酸多态性rs116855232与6-MP所致ALL白细胞减少具有一定的相关性,应引起临床的关注。展开更多
文摘目的 Meta分析探讨NUDT15 c.415C>T位点单核苷酸多态性(SNP)与巯嘌呤类药物所致患者白细胞减少的相关性。方法检索Pubmed、EMbase、中国知网、万方数据库等数据库,同时利用计算机检索、文献追溯等途径收集国内外公开发表的关于NUDT15与巯嘌呤类药物所致白细胞减少的相关性研究文献。检索的文献为截止到2018年2月28日已发表的所有文献。采用NOS标准评价纳入各个原始文献的质量。采用OR值和95%置信区间(CI)来评价NUDT15 c.415C> T和白细胞减少之间的关系。结果纳入7篇研究,共有1 198个接受巯嘌呤类药物治疗的患者。Meta分析结果如下:显性遗传模型(CT+TT vs CC,OR=9.29,95%CI:6.43～13.44,P=0.0001),纯合子模型(TT vs CC,OR=37.32,95%CI:14.199～98.10,P=0.0009),杂合子模型(CT vs CC,OR=7.42,95%CI:5.05～10.88,P=0.0005),隐性遗传模型(TT vs CT,OR=8.79,95%CI:3.497～22.12)。按所有纳入研究的对象Meta分析结果显示,携带T等位基因的NUDT15 c.415C> T与巯嘌呤所导致的白细胞减少的发生具有强相关性(P<0.05)。结论对于巯嘌呤来说,在亚洲人口中,NUDT15 c.415C> T可能是一个高度可信的药物基因预测者。由于该研究纳入的文献数量较少,相关结果需要更多研究予以验证。
基金Supported by National Natural Science Foundation of China,No.81370547 and No.81400642
文摘AIM To observe gene polymorphisms of TPMT and NUDT15, and compare their predictive value for azathioprine(AZA)-induced leukopenia in inflammatory bowel disease(IBD).METHODS This study enrolled 219 patients diagnosed with IBD in Xiangya Hospital, Central South University, Changsha, China from February 2016 to November 2017. Peripheral blood of all patients was collected to detect their genotypes of TPMT and NUDT15 by pyrosequencing at the Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital. Eighty patients were treated with AZA according to the disease condition. During the first month, patients who received AZA underwent routine blood tests and liver function tests once a week. The endpoint of the study was leukopenia induced by AZA. By analyzing patient characteristics, genotypes and leukopenia induced by drug use, we found the risk factors associated with AZA-induced leukopenia.RESULTS There were 219 patients with IBD(160 men and 59 women), including 39 who were confirmed with ulcerative colitis(UC), 176 with Crohn's disease(CD) and 4 with undetermined IBD(UIBD). There were 44 patients(20.1%) with mutant genotype of NUDT15(C/T); among them, 16 received AZA, and 8(50%) developed leukopenia. There were 175 patients(79.7%) with wild genotype of NUDT15(C/C); among them, 64 received AZA, and 11(17.2%) developed leukopenia. A significant difference was found between NUDT15 C/T and its wild-type C/C(P = 0.004). There were only 3 patients with TPMT mutant genotype of A/G(1.4%) who participated in the research, and 1 of them was treated with AZA and developed leukopenia. The remaining 216 patients(98.6%) were found to bear the wild genotype of TPMT(A/A); among them, 79 patients received AZA, and 18(22.8%) developed leukopenia, and there was no significant difference from those with A/G(P = 0.071). The frequency of TPMT mutation was 1.4%, and NUDT15 mutation rate was significantly higher and reached 20.1%(P = 0.000). Therefore, NUDT15 gene polymorphism was obviously a better biomarker than TPMT gene polymorphism in the prediction of AZA-induced leukopenia.CONCLUSION Mutation rate of NUDT15 in Chinese IBD patients is higher than that of TPMT. NUDT15 polymorphism is a better predictor for AZA-induced leukopenia than TPMT polymorphism.
文摘AIM The single nucleotide polymorphism(SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn's disease. Meanwhile, three additional genetic variants of NUDT15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of NUDT15 in patients with inflammatory bowel disease(IBD) treated with thiopurines.METHODS Ninety-six Japanese patients with IBD were enrolled. Genotyping for the NUDT15 and TPMT genes was performed using Custom Taq Man SNP genotyping assays or Sanger sequencing. The changes in white blood cell(WBC) count, mean corpuscular volume(MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR were evaluated.RESULTS Genetic variants of exon 1 and exon 3 of NUDT15 were identified in 24 of 96 patients(25.0%). C.52G > A and c.36_37 insG GAGTC in exon 1 were found in three patients each. All three patients with c.36_37 insG GAGTC in exon 1 were heterozygotes of p.Arg139 Cys in exon 3. Eighteen patients had p.Arg139 Cys in exon 3 alone. The WBC count gradually decreased after initiation of thiopurine treatment in the mutated cases(n = 24), and was significantly lower at 6, 8, 10, and 16 wk(P = 0.0271, 0.0037, 0.0051, and 0.0185, respectively). The WBC counts were also evaluated in patients with and without prednisolone treatment. In the patients with prednisolone treatment, the WBC count tended to show a greater decrease in the mutated cases, with significant differences at 8 and 10 wk(P = 0.012 and 0.029, respectively). In the patients without prednisolone treatment, the WBC count was significantly lower at 2, 4, 8, and 14 wk in mutated cases(P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine treatment in the mutated cases, and was significantly higher at 10 wk(P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR did not differ significantly between the wildtype and mutated cases. TPMT mutations were not found in any of the patients.CONCLUSION Mutations in exon 1 of NUDT15 also affect thiopurineinduced leukopenia in patients with IBD. To discuss thiopurine-induced leukopenia in more detail, investigation of SNPs in both exon 1 and exon 3 of NUDT15 is needed.
文摘目的:系统评价rs116855232与6-巯基嘌呤(6-MP)治疗儿童急性淋巴细胞白血病(ALL)的安全性,旨为临床治疗提供循证医学证据。方法:系统检索PubMed、Web of Science、CNKI和万方数据库,收集有关rs116855232位点多态性与6-MP所致ALL白细胞减少的临床相关研究,利用Stata软件对纳入文献进行Meta分析,计算合并OR值及95%CI。结果:共纳入5项病例对照研究,Meta分析显示rs116855232位点多态性与6-MP所致患者白细胞减少显著相关(P<0.05),其中显性模型(OR=8.06,95%CI:3.40–19.07),纯合子模型(OR=8.20,95%CI:3.14–21.36)以及杂合子模型(OR=7.62,95%CI:1.45–39.98)可以显著增加治疗过程中白细胞减少的风险。然而隐性模型与白细胞减少之间则未发现显著相关性(OR=5.13,95%CI:0.99–26.58);除此之外,我们发现rs116855232可以显著增加患儿早期治疗过程中白细胞计数低于2×10~9的发生率(P<0.05)。结论:NUDT15单核苷酸多态性rs116855232与6-MP所致ALL白细胞减少具有一定的相关性,应引起临床的关注。
