Human thiopurine methyltransferase pharmacogenetics: Gene sequence polymorphisms
Human thiopurine methyltransferase pharmacogenetics: Gene sequence polymorphisms
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DOI：
10.1016/s0009-9236(97)90152-1
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发表时间：
1997-07-01
影响因子：
6.7
通讯作者：
Weinshilboum, R
中科院分区：
文献类型：
--
作者：
Otterness, D;Szumlanski, C;Weinshilboum, R
巯基嘌呤甲基转移酶（TPMT）催化巯基嘌呤药物的S-甲基化。TPMT活性受一种常见的遗传多态性调节，该多态性与巯基嘌呤毒性和疗效的较大个体差异相关。我们以前克隆了人类TPMT的功能基因，并报告了一种常见的低酶活性变体等位基因TPMT*3A，其在cDNA核苷酸460和719处含有点突变。在本研究中，我们着手确定美国临床实验室样本中与低酶活性相关的TPMT变异等位基因的数量、类型和频率，并将这些结果与从两个不同种族群体获得的数据进行比较。我们在研究的283份临床实验室样本中总共发现了6种不同的低TPMT活性变体等位基因。最常见的变异是 *3A;第二常见的变异等位基因 *3C仅包含核苷酸719多态性;检测到其他四种变异等位基因。TPMT*3A似乎也是挪威白色人群样本中最常见的变异等位基因，但在韩国儿童人群样本中未发现。然而，*3C存在于韩国儿童的样本中，还有一个新的等位基因 *6。表征低TPMT酶活性的变异等位基因将有助于评估基于脱氧核糖核酸的诊断测试用于确定TPMT基因型的潜在临床效用。
Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT activity is regulated by a common genetic polymorphism that is associated with large individual variations in thiopurine toxicity and efficacy. We previously cloned the functional gene for human TPMT and reported a common variant allele for low enzyme activity, TPMT*3A, that contains point mutations at cDNA nucleotides 460 and 719. In the present study, we set out to determine the number, types, and frequencies of TPMT variant alleles associated with low enzyme activity in clinical laboratory samples in the United States and to compare those results with data obtained from two different ethnic groups. We identified a total of six different variant alleles for low TPMT activity in the 283 clinical laboratory samples studied. The most common variant was *3A; the second most frequent variant allele, *3C, contained only the nucleotide 719 polymorphism; and four other variant alleles were detected. TPMT*3A also appeared to be the most common variant allele in a Norwegian white population sample, but it was not found in a population sample of Korean children. However, *3C was present in samples from the Korean children, as was a novel allele, *6. Characterization of variant alleles for low TPMT enzyme activity will help make it possible to assess the potential clinical utility of deoxyribonucleic acid-based diagnostic tests for determining TPMT genotype.