Takatsu Noritaka, Matsui Toshiyuki, Murakami Yuji, Ishihara Hiroshi, Hisabe Takashi, Nagahama Takashi, Maki Shinichirou, Beppu Takahiro, Takaki Yasuhiro, Hirai Fumihito, Yao Kenshi
Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan.
J Gastroenterol Hepatol. 2009 Jul;24(7):1258-64. doi: 10.1111/j.1440-1746.2009.05917.x.
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.
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).
Of the 147 patients, 144 (98.0%) were wild-type for TPMT (TPMT*1/1) and three (2.0%) carried a mutant TPMT allele (TPMT1/*3C). The incidence of adverse reactions was 33.3% (38/114) in the wild-type group. Leukopenia (WBC < or = 3000/microL) 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).
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.
硫唑嘌呤（AZA）不良反应发生率较高。我们检测了硫嘌呤甲基转移酶（TPMT）基因多态性，以确定TPMT基因型是否可作为预测AZA不良反应发生的标志物。
回顾性研究147例日本炎症性肠病（IBD）患者中TPMT突变的频率。通过直接测序确定这些受试者中四种突变等位基因（TPMT*2、*3B、3C和8）的存在情况。研究携带野生型TPMT患者的不良反应发生率。对47例野生型TPMT患者的6-硫鸟嘌呤核苷酸（6-TGN）血药浓度进行测定和分析。结合氨基水杨酸类药物（ASA）的联合使用情况对结果进行分析。
147例患者中，144例（98.0%）为TPMT野生型（TPMT*1/1），3例（2.0%）携带突变型TPMT等位基因（TPMT1/*3C）。野生型组不良反应发生率为33.3%（38/114）。野生型TPMT患者中15.8%出现白细胞减少（白细胞计数≤3000/μL）。47例野生型TPMT患者的6-TGN水平各不相同。与未接受ASA联合治疗的患者相比，接受ASA联合治疗的患者血药浓度显著更高（P = 0.0033）。
日本IBD患者中TPMT基因突变频率较低。即使是携带野生型TPMT的患者，AZA不良反应发生率也较高。得出结论，在日本IBD患者中，检测TPMT基因型可能无助于预测AZA不良反应。
