Haglund Sofie, Lindqvist Malin, Almer Sven, Peterson Curt, Taipalensuu Jan
Division of Research and Development in Laboratory Medicine, Ryhov County Hospital, SE-551 85 Jönköping, Sweden.
Clin Chem. 2004 Feb;50(2):288-95. doi: 10.1373/clinchem.2003.023846. Epub 2003 Dec 4.
Interindividual differences in therapeutic efficacy in patients treated with thiopurines might be explained by the presence of thiopurine S-methyltransferase (TPMT) alleles that encode for reduced TPMT enzymatic activity. It is therefore of value to know an individual's inherent capacity to express TPMT.
We developed a pyrosequencing method to detect 10 single-nucleotide polymorphisms (SNPs) in TPMT. A Swedish population (n = 800) was examined for TPMT3A, TPMT3B, TPMT3C, and TPMT2. Patients with inflammatory bowel disease (n = 24) and healthy volunteers (n = 6), selected on the basis of TPMT enzymatic activity, were investigated for all 10 SNPs to determine the relationship between TPMT genotype and phenotype.
In the general population we identified the following genotypes with nonfunctional alleles: TPMT*1/*3A (3A allelic frequency, 3.75%), TPMT1/*3C (3C allelic frequency, 0.44%), TPMT1/*3B (3B allelic frequency, 0.13%), and TPMT1/*2 (2 allelic frequency, 0.06%). All nine individuals with normal enzymatic activity were wild-type TPMT1/1. Thirteen individuals with intermediate activity were either TPMT1/3A (n = 12) or TPMT1/2 (n = 1). Eight individuals with low enzymatic activity were TPMT3A/3A (n = 4), TPMT3A/3C (n = 2), or TPMT1/*3A (n = 2).
Next to wild type, the most frequent alleles in Sweden are TPMT3A and TPMT3C. A previously established phenotypic cutoff for distinguishing normal from intermediate metabolizers was confirmed. To identify the majority of cases (90%) with low or intermediate TPMT activity, it was sufficient to analyze individuals for only 3 of the 10 SNPs investigated. Nevertheless, this investigation indicates that other mutations might be of relevance for decreased enzymatic activity.
硫嘌呤治疗患者的个体治疗效果差异可能由编码硫嘌呤 S - 甲基转移酶（TPMT）活性降低的等位基因所致。因此，了解个体表达 TPMT 的内在能力具有重要意义。
我们开发了一种焦磷酸测序方法来检测 TPMT 中的 10 个单核苷酸多态性（SNP）。对一个瑞典人群（n = 800）检测了 TPMT3A、TPMT3B、TPMT3C 和 TPMT2。根据 TPMT 酶活性选择的炎症性肠病患者（n = 24）和健康志愿者（n = 6），对所有 10 个 SNP 进行研究以确定 TPMT 基因型与表型之间的关系。
在一般人群中，我们鉴定出具有无功能等位基因的以下基因型：TPMT*1/*3A（3A 等位基因频率为 3.75%）、TPMT1/*3C（3C 等位基因频率为 0.44%）、TPMT1/*3B（3B 等位基因频率为 0.13%）和 TPMT1/*2（2 等位基因频率为 0.06%）。所有酶活性正常的 9 个人均为野生型 TPMT1/1。13 个酶活性中等的个体为 TPMT1/3A（n = 12）或 TPMT1/2（n = 1）。8 个酶活性低的个体为 TPMT3A/3A（n = 4）、TPMT3A/3C（n = 2）或 TPMT1/*3A（n = 2）。
除野生型外，瑞典最常见的等位基因是 TPMT3A 和 TPMT3C。确认了先前确定的区分正常代谢者与中间代谢者的表型临界值。为了识别大多数（90%）TPMT 活性低或中等的病例，仅分析所研究的 10 个 SNP 中的 3 个就足够了。然而，这项研究表明其他突变可能与酶活性降低有关。
