Thiopurine Methyltransferase Gene Polymorphisms in Chinese Patients with Inflammatory Bowel Disease
Thiopurine Methyltransferase Gene Polymorphisms in Chinese Patients with Inflammatory Bowel Disease
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DOI：
10.1159/000205268
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发表时间：
2009-01-01
期刊：
影响因子：
3.2
通讯作者：
Si, Jianmin
中科院分区：
文献类型：
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作者：
Cao, Qian;Zhu, Qin;Si, Jianmin
背景：硫代嘌呤类药物硫唑嘌呤和6-巯基嘌呤在炎症性肠病(IBD)的治疗中得到了很好的应用。然而，这些药物的疗效和毒性在患者之间存在很大的变异性，这是硫嘌呤甲基转移酶(TPMT)基因多态的结果。本研究的目的是确定中国IBD患者TPMT基因的多态性，并探讨TPMT状态与硫代嘌呤相关毒性的关系。材料和方法：入选IBD患者189例，其中克罗恩病87例，溃疡性结肠炎102例，健康对照组273例。所有受试者均来自中国汉族。用等位基因特异性聚合酶链式反应和聚合酶链式反应-限制性片段长度多态性分析TPMT*2、*3A、*3B和*3C基因的多态性。用直接测序的方法确认突变结果。对硫唑嘌呤中毒患者的TPMT基因外显子进行扩增和测序，以检测TPMT突变。结果：未检测到TPMT*2、*3A、*3B突变等位基因。IBD组TPMT*3C等位基因频率为1.59%，与健康对照组(1.59%vs.1.47%)相似(P=1.000)。硫唑嘌呤治疗43例，4例出现骨髓毒性，1例出现肝毒性，药物毒性发生率为11.7%(5/43)。在这5例患者中未检测到TPMT*2、*3A、*3B或*3C基因多态。对这5例患者的TPMT基因外显子直接测序后，在3例患者中发现了不改变编码氨基酸的同义单核苷酸多态(TPMT*1S)。结论：TPMT*3C可能是该汉族人群中唯一的变异等位基因。该人群TPMT变异等位基因的总频率低于高加索人群，但中国汉族人IBD患者的硫代嘌呤毒性并不低。TPMT基因多态以外的其他因素可能是毒性形成的原因。版权所有(C)2009年S.Karger AG，巴塞尔
Background: The thiopurine drugs azathioprine and 6-mercaptopurine are well established in the treatment of inflammatory bowel disease (IBD). However, great interpatient variability exists in the efficacy and toxicity of the drugs, and this results from thiopurine methyltransferase (TPMT) gene polymorphisms. The aim of this study was to identify the TPMT gene polymorphisms in Chinese IBD patients and to study the relationship between TPMT status and thiopurine-related toxicity in these patients. Materials and Methods: A total of 189 IBD patients, 87 with Crohn's disease and 102 with ulcerative colitis, and 273 healthy controls were enrolled. All subjects were from the Han Chinese ethnic group. Polymorphisms in TPMT*2, *3A, *3B and *3C were analyzed using allele-specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. Direct sequencing was used to confirm the mutation results. Exons of the TPMT gene from patients who suffered from azathioprine-induced toxicity were amplified and sequenced to detect TPMT mutations. Results: No TPMT*2, *3A or *3B mutant alleles were detected. The allele frequency of TPMT*3C in the IBD group was 1.59%, which was similar to that of the healthy control group (1.59 vs. 1.47%, p = 1.000). Forty-three patients were treated with azathioprine therapy, 4 experienced myelotoxicity, and 1 experienced hepatotoxicity, so the incidence of drug toxicity was 11.7% (5/43). No TPMT*2, *3A, *3B or *3C polymorphisms were detected in these 5 patients. After directly sequencing the exons of the TPMT gene in these 5 patients, a synonymous single-nucleotide polymorphism (TPMT*1S), which does not alter the encoded amino acid, was found in 3 patients. Conclusion: TPMT*3C seemed to be a unique variant allele in this Han Chinese population. The overall frequencies of variant TPMT alleles in this population were lower than those in Caucasians, but thiopurine toxicity in Han Chinese IBD patients is not low. Factors other than TPMT polymorphisms may be responsible for the development of toxicity. Copyright (c) 2009 S. Karger AG, Basel