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
Context: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for c hildren with acute lymphoblastic leukemia (ALL). Thiopurine...Context: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for c hildren with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (T PMT) is involved in the metabolism of mercaptopurine and subject to genetic poly morphism, with heterozygous individuals having intermediate and homozygous mutan t individuals having very low TPMT activity. Objective: To assess the associatio n of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. Design, Set ting, and Patients: TPMT genotyping of childhood ALL patients (n = 814) in Germa ny consecutively enrolled in the ALLBFM (Berlin- Frankfurt- Mü nster) 2000 study from October 1999 to September 2002. Minima l residual disease was analyzed on treatment days 33 and 78 for riskadapted trea tment stratification. A 4- week cycle of mercaptopurine was administered betwee n these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analys es. Main Outcome Measures: Minimal residual disease load before (day 33) and aft er (day 78) mercaptopurine treatment. Loads smaller than 10- 4 were defined as negative. Results: Patients (n = 55) heterozygous for allelic variants of TPMT c onferring lower enzyme activity had a signifi- cantly lower rate of minimal res idual disease positivity (9.1 % ) compared with patients (n = 755) with homozyg ous wild- type alleles (22.8% ) on day 78 (P = .02). This translated into a 2. 9- fold reduction in risk for patients with wild- type heterozygous alleles (r elative risk, 0.34; 95% confidence interval, 0.13- 0.86). Conclusions: TPMT g enotype has a substantial impact on minimal residual disease after administratio n of mercaptopurine in the early course of childhood ALL, most likely through mo dulation of mercaptopurine dose intensity. Our findings support a role for minim al residual disease analyses in the assessment of genotypephenotype associations in multiagent chemotherapeutic trials.展开更多
目的研究硫嘌呤甲基转移酶（thiopurine S-methyltransferase，TPMT）基因编码区突变及多态性在急性白血病（acute leukemia，AL）患儿和健康儿童中的分布情况。方法应用逆转录聚合酶链变性梯度凝胶电泳结合DNA直接测序技术，对53例AL...目的研究硫嘌呤甲基转移酶（thiopurine S-methyltransferase，TPMT）基因编码区突变及多态性在急性白血病（acute leukemia，AL）患儿和健康儿童中的分布情况。方法应用逆转录聚合酶链变性梯度凝胶电泳结合DNA直接测序技术，对53例AL患儿和115名健康儿童的cDNAs进行了TPMT突变及多态性的筛查与鉴定，分析各基因型在两组之间的分布差异。结果在健康儿童组TPM丁中发现2个国内外未见报道的基因突变位点：210C〉T（C70C）和622T〉C（F208L）杂合子各1例，提交至GenBankdbsNP，分别获NCBI—SS序列号：107796292、107795933。鉴定了2种已知的编码区单核苷酸多态性（single—nucleotide polymorphisms within the coding region，cSNPs），474T〉C（11581）即TPMT＊1S和719A〉G（T240C）即TPMT＊3C在中国AL患儿及健康儿童中的等位基因频率，分别为14．2％，2．83％与17．0％，3．04％，等位基因总频率分别为16．2％，2．99％。两种cSNPs在两组人群的等位基因频率差异无统计学意义。结论发现了两个新的基因突变位点，提供了为预测不同个体间对硫嘌呤类药物潜在敏感性差异的遗传学标志。确定了两种已知cSNPs在中国AL患儿及健康儿童中的基因型分布和等位基因频率，发现它们与白血病的易感性无相关性。展开更多
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Context: Early response to multiagent chemotherapy, including mercaptopurine, as measured by minimal residual disease is an important prognostic factor for c hildren with acute lymphoblastic leukemia (ALL). Thiopurine methyltransferase (T PMT) is involved in the metabolism of mercaptopurine and subject to genetic poly morphism, with heterozygous individuals having intermediate and homozygous mutan t individuals having very low TPMT activity. Objective: To assess the associatio n of TPMT genotype with minimal residual disease load before and after treatment with mercaptopurine in the early treatment course of childhood ALL. Design, Set ting, and Patients: TPMT genotyping of childhood ALL patients (n = 814) in Germa ny consecutively enrolled in the ALLBFM (Berlin- Frankfurt- Mü nster) 2000 study from October 1999 to September 2002. Minima l residual disease was analyzed on treatment days 33 and 78 for riskadapted trea tment stratification. A 4- week cycle of mercaptopurine was administered betwee n these 2 minimal residual disease measurements. Patients (n = 4) homozygous for a mutant TPMT allele, and consequently deficient in TPMT activity, were treated with reduced doses of mercaptopurine and, therefore, not included in the analys es. Main Outcome Measures: Minimal residual disease load before (day 33) and aft er (day 78) mercaptopurine treatment. Loads smaller than 10- 4 were defined as negative. Results: Patients (n = 55) heterozygous for allelic variants of TPMT c onferring lower enzyme activity had a signifi- cantly lower rate of minimal res idual disease positivity (9.1 % ) compared with patients (n = 755) with homozyg ous wild- type alleles (22.8% ) on day 78 (P = .02). This translated into a 2. 9- fold reduction in risk for patients with wild- type heterozygous alleles (r elative risk, 0.34; 95% confidence interval, 0.13- 0.86). Conclusions: TPMT g enotype has a substantial impact on minimal residual disease after administratio n of mercaptopurine in the early course of childhood ALL, most likely through mo dulation of mercaptopurine dose intensity. Our findings support a role for minim al residual disease analyses in the assessment of genotypephenotype associations in multiagent chemotherapeutic trials.
文摘目的研究硫嘌呤甲基转移酶（thiopurine S-methyltransferase，TPMT）基因编码区突变及多态性在急性白血病（acute leukemia，AL）患儿和健康儿童中的分布情况。方法应用逆转录聚合酶链变性梯度凝胶电泳结合DNA直接测序技术，对53例AL患儿和115名健康儿童的cDNAs进行了TPMT突变及多态性的筛查与鉴定，分析各基因型在两组之间的分布差异。结果在健康儿童组TPM丁中发现2个国内外未见报道的基因突变位点：210C〉T（C70C）和622T〉C（F208L）杂合子各1例，提交至GenBankdbsNP，分别获NCBI—SS序列号：107796292、107795933。鉴定了2种已知的编码区单核苷酸多态性（single—nucleotide polymorphisms within the coding region，cSNPs），474T〉C（11581）即TPMT＊1S和719A〉G（T240C）即TPMT＊3C在中国AL患儿及健康儿童中的等位基因频率，分别为14．2％，2．83％与17．0％，3．04％，等位基因总频率分别为16．2％，2．99％。两种cSNPs在两组人群的等位基因频率差异无统计学意义。结论发现了两个新的基因突变位点，提供了为预测不同个体间对硫嘌呤类药物潜在敏感性差异的遗传学标志。确定了两种已知cSNPs在中国AL患儿及健康儿童中的基因型分布和等位基因频率，发现它们与白血病的易感性无相关性。
