摘要
目的 探讨风湿病患者硫嘌呤甲基转移酶（TPMT）基因型与硫唑嘌呤耐受性的关系。方法采用等位基因特异性的聚合酶链反应（AS-PCR）方法和聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法检测200例风湿病患者4种常见TPMT突变等位基因TPMT^＊2（G238C）、TPMT^＊3A（A719G／G460A）、TPMT^＊3B（G460A）和TPMT^＊3C（A719G）。194例患者使用了硫唑嘌呤（剂量50～150mg／d），并随访观察3个月。结果在200例风湿病患者中检测到4例TPMT^＊3C杂合子，没有检测到TPMT^＊2、TPMT^＊3B、TPMT^＊3A型突变。基因型频率：野生型基因纯合子为98％，杂合子TPMT^＊1／TPMT^＊3C为2％。风湿病患者突变等位基因频率为1％。4例TPMT^＊3C杂合子TPMT活性平均值为（2．44±1．2）U／ml红细胞，196例野生型基因纯合子TPMT活性平均值为（12．24±6．8）U／ml红细胞。TPMT^＊3C杂合子的酶活性均值显著低于野生型基因纯合子，差异有统计学意义。194例使用硫唑嘌呤的患者中18例出现骨髓抑制，2例为严重造血系统危象，6例合并出现肝功能损害。4例TPMT^＊3C杂合子患者除1例未使用硫唑嘌呤外，其余3例均在用药后1个月内出现骨髓抑制，包括2例严重造血系统危象。结论存在TPMT突变等位基因的患者对硫唑嘌呤不耐受，可能发生严重造血系统危象。在用药前检测TPMT基因型对提高治疗的安全性有重要意义。
Objective To discuss the relationship between the genotype of thiopurine methyltransferase （TPMT） and azathioprine tolerance in the patients with rheumatic diseases. Methods Four common mutation alleles of TPMT in 200 patients with rheumatic diseases [TPMT^＊ 2 （ G238C ） , TPMT^＊ 3A（ A719G/G460A）, TPMT^＊ 3B（ G460A）, TPMT ^＊ 3C （A719G） ] were detected by allele specific polymerase chain reaction （AS-PCR） and polymerase chain reaction-restriction fragment length polymorphism （PCR-PFLP） . 194 patients who had used azathioprine finished the 3 months＇ followup. Results In the 200 patients with rheumatic diseases, 4 cases of heterozygote of TPMT^＊3C were detected, but no mutation of TPMT^＊ 2, TPMT^＊3B or TPMT^＊3A was found. The genotypic frequency of wild- type homozygote was 98%, and that of heterozygote （TPMT^＊1/TPMT^＊3C ） was 2%. Mutation allele frequency in these patients was 1%. Average of TPMT activity of the 4 cases of heterozygote was （2.4±1.2） U/ml red blood cells, significantly lower than that of the 196 cases of homozygote which was （ 12.2±6. 8） U/ml RBC. In the 194 patients who had used azathioprine, bone marrow suppression occurred in 18 patients, 2 of which suffered severe crisis of hematopoietic system, and 6 of which were complicated with impaired liver function. In the 4 patients with heterozygote, 3 had used azathioprine, and bone marrow suppression occurred within 1 month of using the drug, including 2 cases of severe crisis of hematopoietic system. Conclusion Patients with mutation alleles of TPMT are intolerant to azathioprine, and likely to have severe crisis of hematopoietic system. To detect the TPMT genotype before using azathioprine is significant to improve the therapeutic safety.
出处
《中华医学杂志》
CAS
CSCD
北大核心
2007年第25期1734-1737,共4页
National Medical Journal of China
基金
广东省科技计划基金(2003C34003)
广东省医学科研基金(B2005025)
广东省 科技计划基金(2005B30701001)
