Bahrehmand Fariborz, Vaisi-Raygani Asad, Kiani Amir, Bashiri Homayoun, Zobeiri Mahdi, Tanhapour Maryam, Pourmotabbed Tayebeh
Clin Lab. 2017 May 1;63(5):947-954. doi: 10.7754/Clin.Lab.2017.161201.
Thiopurine methyl transferase (TPMT), a drug-metabolizing enzyme, catalyzes methylation and consequently, the metabolism of thiopurine compounds used for treatment of inflammatory bowel disease (IBD). Individuals who are homozygous recessive or have extremely low TPMT activity need to avoid thiopurines because of concern for significant leukopenia. The aim of this research was to determine TPMT phenotypes and genotypes in IBD patients to predict the risk of thiopurine toxicity before treatment.
The present case-control study consisted of 210 ulcerative colitis patients and 212 unrelated healthy controls from the population of western Iran. TPMT phenotype and genotype were determined by HPLC and allele specific PCR and PCR-RFLP, respectively.
TPMT phenotyping and genotyping were compatible and demonstrated no frequency for deficient, 2.2% for low, and 97.8% for normal-activity which is different compared with the results of other studies. There was a significant negative correlation between TPMT activities as calculated based on nmol6MTG/gHb/h and the Hb levels in both UC (r = -0.54, p < 0.001) and control groups (r = -0.27, p < 0.001). Interestingly, a significant positive correlation between Hb levels and TPMT activities was seen when the enzyme activity was calculated in mU/L in both UC patients (r = 0.14, p = 0.05) and in control subjects (r = 0.43, p < 0.001). The overall concordance rate between TPMT phenotypes and genotypes of mutants to alleles (9 out of 422), based on receiver-operating characteristic (ROC) curve, yielded a sensitivity of 94.7% and specificity of 90% for mU/L and a sensitivity of 85.6% and specificity of 90% for nmol6MTG/gHb/h.
The use of mU/L is more appropriate than nmol6MTG/gHb/h for expressing TPMT activity, and there is better correlation between genotypes and phenotypes of TPMT based on mU/L. The frequency of known mutant TPMT alleles in western Iran (Kurd population) is low suggesting low risk of thiopurine drug toxicity in IBD patients from this region.
硫嘌呤甲基转移酶（TPMT）是一种药物代谢酶，催化甲基化反应，进而参与用于治疗炎症性肠病（IBD）的硫嘌呤化合物的代谢。纯合隐性个体或TPMT活性极低的个体因担心会出现严重白细胞减少症而需要避免使用硫嘌呤。本研究的目的是确定IBD患者的TPMT表型和基因型，以预测治疗前硫嘌呤毒性的风险。
本病例对照研究纳入了来自伊朗西部人群的210例溃疡性结肠炎患者和212名无亲缘关系的健康对照。分别通过高效液相色谱法（HPLC）以及等位基因特异性PCR和PCR-RFLP法确定TPMT表型和基因型。
TPMT表型分析和基因分型结果相符，结果显示缺陷型频率为零，低活性型为2.2%，正常活性型为97.8%，这与其他研究结果不同。基于nmol6MTG/gHb/h计算的TPMT活性与UC组（r = -0.54，p < 0.001）和对照组（r = -0.27，p < 0.001）的血红蛋白（Hb）水平之间均存在显著负相关。有趣的是，当以mU/L计算酶活性时，UC患者（r = 0.14，p = 0.05）和对照受试者（r = 0.43，p < 0.001）的Hb水平与TPMT活性之间均存在显著正相关。基于受试者工作特征（ROC）曲线，TPMT表型与突变体至等位基因的基因型之间的总体一致性率（422例中有9例）显示，以mU/L计算时敏感性为94.7%，特异性为90%；以nmol6MTG/gHb/h计算时敏感性为85.6%，特异性为90%。
用mU/L表示TPMT活性比nmol6MTG/gHb/h更合适，基于mU/L的TPMT基因型与表型之间的相关性更好。伊朗西部（库尔德人群）已知的TPMT突变等位基因频率较低，这表明该地区IBD患者发生硫嘌呤药物毒性的风险较低。
