Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease
Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease
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DOI：
10.1111/j.1440-1746.2009.05917.x
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发表时间：
2009-07-01
影响因子：
4.1
通讯作者：
Yao, Kenshi
中科院分区：
文献类型：
--
作者：
Takatsu, Noritaka;Matsui, Toshiyuki;Yao, Kenshi
背景和目的：硫唑嘌呤（AZA）与高频率的不良反应相关。我们研究了硫嘌呤S-甲基转移酶（TPMT）基因的多态性，以确定TPMT基因型是否会成为一个预测指标的发展不良反应AZA.Methods：TPMT突变的频率进行了调查，在147日本炎症性肠病（IBD）患者回顾性。在这些受试者中，通过直接测序确定了四种突变等位基因（TPMT*2、*3B、*3C和 *8）的存在。对携带野生型TPMT患者的不良反应发生率进行了调查。本文对47例TPMT野生型患者的血6-硫代鸟嘌呤核苷酸（6-TGN）水平进行了检测和分析。结果：147例患者中，144例（98.0%）为野生型TPMT（TPMT*1/*1），3例（2.0%）携带突变型TPMT等位基因（TPMT*1/*3C）。野生型组不良反应发生率为33.3%（38/114）。野生型TPMT患者白细胞减少（WBC < 3000/μ L）发生率为15.8%。6-47例野生型TPMT患者的TGN水平各不相同。阿萨联合治疗组患者血中6-TGN水平显著高于阿萨未联合治疗组（P = 0.0033）。结论：日本IBD患者TPMT基因突变频率较低。AZA不良反应的发生率很高，即使是携带野生型TPMT的患者。结论是，TPMT基因型的测定可能不是有用的，在日本IBD患者预测不良反应AZA。
Background and Aims:Azathioprine (AZA) is associated with a high frequency of adverse reactions. We examined polymorphism of the thiopurine S-methyltransferase (TPMT) gene to determine whether the TPMT genotype would be a predictive marker for the development of adverse reactions to AZA.Methods:The frequency of TPMT mutations was investigated in 147 Japanese inflammatory bowel disease (IBD) patients retrospectively. In these subjects, the presence of four mutant alleles (TPMT*2, *3B, *3C and *8) was determined by direct sequencing. The incidence of adverse reactions among patients carrying wild-type TPMT was investigated. The blood level of 6-thioguanine nucleotide (6-TGN) was measured and analyzed in 47 patients with wild-type TPMT. The results were analyzed in relation to the concomitant use of aminosalicylates (ASA).Results:Of the 147 patients, 144 (98.0%) were wild-type for TPMT (TPMT*1/*1) and three (2.0%) carried a mutant TPMT allele (TPMT*1/*3C). The incidence of adverse reactions was 33.3% (38/114) in the wild-type group. Leukopenia (WBC < 3000/mu L) was seen in 15.8% of the patients with wild-type TPMT. 6-TGN levels varied among 47 patients with wild-type TPMT. The blood levels of 6-TGN were significantly higher in the patients receiving concomitant ASA treatment compared with those not receiving concomitant ASA treatment (P = 0.0033).Conclusion:The frequency of TPMT gene mutations is low among Japanese IBD patients. The incidence of adverse reactions to AZA was high, even in patients carrying wild-type TPMT. It is concluded that determination of TPMT genotype may not be useful in Japanese IBD patients to predict adverse reactions to AZA.