Collie-Duguid E S, Pritchard S C, Powrie R H, Sludden J, Collier D A, Li T, McLeod H L
The University of Aberdeen, Department of Medicine and Therapeutics, Institute of Medical Sciences, Foresterhill, UK.
Pharmacogenetics. 1999 Feb;9(1):37-42. doi: 10.1097/00008571-199902000-00006.
Thiopurine methyltransferase metabolizes 6-mercaptopurine, thioguanine and azathioprine, thereby regulating cytotoxicity and clinical response to these thiopurine drugs. In healthy Caucasian populations, 89-94% of individuals have high thiopurine methyltransferase activity, 6-11% intermediate and 0.3% low, resulting from genetic polymorphism. Four variant thiopurine methyltransferase alleles were detected in over 80% of individuals with low or intermediate thiopurine methyltransferase activity. The wild-type allele is defined as TPMT1 and the mutant alleles are TPMT2 (G238C), TPMT3A (G460A and A719G), TPMT3B (G460A) and TPMT3B (A719G). The frequency of these alleles in different ethnic groups is not well defined. In this study, DNA from 199 British Caucasian, 99 British South West Asian and 192 Chinese individuals was analysed for the presence of these variant alleles using polymerase chain reaction-restriction fragment length polymorphism and allele-specific polymerase chain reaction based assays. The frequency of individuals with a variant thiopurine methyltransferase genotype was: Caucasians 10.1% (20/199), South West Asians 2.0% (2/99) and Chinese 4.7% (9/192). Two TPMT2 heterozygotes were identified in the Caucasian population, but this allele was not found in the two Asian populations. TPMT3A was the only mutant allele found in the South West Asians (two heterozygotes). This was also the most common mutant allele in the Caucasians (16 heterozygotes and one homozygote) but was not found in the Chinese. All mutant alleles identified in the Chinese population were TPMT3C (nine heterozygotes). This allele was found at a low frequency in the Caucasians (one heterozygote). This suggests that A719G is the oldest mutation, with G460A being acquired later to form the TPMT3A allele in the Caucasian and South West Asian populations. TPMT2 appears to be a more recent allele, which has only been detected in Caucasians to date. These ethnic differences may be important in the clinical use of thiopurine drugs.
硫嘌呤甲基转移酶可代谢6-巯基嘌呤、硫鸟嘌呤和硫唑嘌呤，从而调节对这些硫嘌呤类药物的细胞毒性和临床反应。在健康的白种人群中，89% - 94%的个体具有高硫嘌呤甲基转移酶活性，6% - 11%为中等活性，0.3%为低活性，这是由基因多态性导致的。在80%以上硫嘌呤甲基转移酶活性低或中等的个体中检测到四种硫嘌呤甲基转移酶变异等位基因。野生型等位基因定义为TPMT1，突变等位基因为TPMT2（G238C）、TPMT3A（G460A和A719G）、TPMT3B（G460A）和TPMT3C（A719G）。这些等位基因在不同种族群体中的频率尚不明确。在本研究中，使用聚合酶链反应 - 限制性片段长度多态性和基于等位基因特异性聚合酶链反应的检测方法，对199名英国白种人、99名英国西南亚人和192名中国人的DNA进行分析，以检测这些变异等位基因的存在。硫嘌呤甲基转移酶基因型变异个体的频率分别为：白种人10.1%（20/199），西南亚人2.0%（2/99），中国人4.7%（9/192）。在白种人群体中鉴定出两名TPMT2杂合子，但在两个亚洲群体中未发现该等位基因。TPMT3A是在西南亚人中发现的唯一突变等位基因（两名杂合子）。这也是白种人中最常见的突变等位基因（16名杂合子和一名纯合子），但在中国人中未发现。在中国人群体中鉴定出的所有突变等位基因均为TPMT3C（九名杂合子）。该等位基因在白种人中以低频率出现（一名杂合子）。这表明A719G是最古老的突变，G460A是后来在白种人和西南亚人群体中获得的，从而形成了TPMT3A等位基因。TPMT2似乎是一个较新的等位基因，迄今为止仅在白种人中检测到。这些种族差异在硫嘌呤类药物的临床应用中可能很重要。
