Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
J Crohns Colitis. 2012 Jul;6(6):655-9. doi: 10.1016/j.crohns.2011.11.014. Epub 2011 Dec 13.
A pre-treatment determination of the thiopurine S-methyltransferase (TPMT) genotype or phenotype can identify patients at risk of developing severe adverse reactions from thiopurine treatment. The risk of misclassifying a patient might be dependent on the method used. The aim of this study was to investigate the concordance between TPMT genotyping and phenotyping.
The data consist of 7195 unselected and consecutive TPMT genotype and phenotype determinations sent to the division of Clinical Pharmacology, Linköping, Sweden. TPMT activity was measured in red blood cells (RBC) and the genotype determined by pyrosequencing for the three most common TPMT variants (TPMT *2, *3A, *3C).
TPMT genotyping identified 89% as TPMT wild type (*1/*1), 10% as TPMT heterozygous and 0.5% as TMPT defective. The overall concordance between genotyping and phenotyping was 95%, while it was 96% among IBD patients (n=4024). Genotyping would have misclassified 8% of the TPMT defectives as heterozygous as compared to 11% if only TPMT activity had been measured. 11% of the heterozygous patients had a normal TPMT activity (>8.9 U/ml RBC) and 3% of the TPMT wild-type patients had an intermediate TPMT activity (2.5-8.9 U/ml RBC).
There is a risk for TPMT misclassification when only genotyping or phenotyping is used, but it is not reasonable to check both in all patients. Since TPMT genotyping is the more reliable test, especially in TPMT heterozygotes, we suggest that genotyping should be considered the primary choice for the pre-treatment evaluation of TPMT function before initiation of thiopurine therapy.
硫嘌呤甲基转移酶（TPMT）基因型或表型的预处理测定可以识别出有发生硫嘌呤治疗严重不良反应风险的患者。错误分类患者的风险可能取决于所使用的方法。本研究旨在探讨 TPMT 基因分型和表型之间的一致性。
该数据包括 7195 例未经选择且连续的 TPMT 基因型和表型测定结果，这些结果被送到瑞典林雪平临床药理学系。红细胞（RBC）中的 TPMT 活性通过焦磷酸测序进行测定，同时对三种最常见的 TPMT 变体（TPMT*2、3A 和3C）进行基因分型。
TPMT 基因分型将 89%的患者鉴定为 TPMT 野生型（*1/*1），10%为 TPMT 杂合子，0.5%为 TPMT 缺陷型。基因分型与表型之间的总体一致性为 95%，而在 IBD 患者（n=4024）中则为 96%。与仅测量 TPMT 活性相比，基因分型会将 8%的 TPMT 缺陷型错误分类为杂合子，而将 11%的杂合子患者的 TPMT 活性鉴定为正常（>8.9 U/ml RBC），将 3%的 TPMT 野生型患者的 TPMT 活性鉴定为中间型（2.5-8.9 U/ml RBC）。
仅进行基因分型或表型测定时，TPMT 存在分类错误的风险，但在所有患者中同时检查并不合理。由于 TPMT 基因分型是一种更可靠的检测方法，尤其是在 TPMT 杂合子中，因此我们建议在开始硫嘌呤治疗前，将基因分型作为 TPMT 功能的预处理评估的首选方法。
