背景:硫唑嘌呤(aza)治疗对炎症性肠病的治疗有益,但10%-30%的患者由于药物不良反应而不能耐受aza治疗。硫嘌呤S-甲基转移酶(TPMT)缺乏症易导致骨髓毒性,但其与其他副作用的关联尚不清楚。肌苷三磷酸酶(ITPA)突变是其他可能参与硫嘌呤代谢和耐受性的药物遗传多态性。
方法:我们分析了一项为期6个月的前瞻性研究的数据,该研究包括71例首次接受aza不耐受治疗的克罗恩病患者。对患者进行了常见TPMT和ITPA突变的基因分型,并测量了治疗前的TPMT活性。
结果:aza治疗早期退出(2周内)与ITPA94C>A相关[P=0.020;比值比(OR),4.6;95%置信区间(95%CI),1.2-17.4]和低TPMT活性[<10nmol/(mL红细胞。h);P=0.007;OR=5.5;95%CI,1.6-19.2]。由ITPA94C>A或TPMT<10nmol/(mL红细胞。h)与早期退出(P=0.001;OR=11.3;95%CI,2.5-50.0)和所有退出(P=0.002;OR=4.8;95%CI,1.8-13.3)显着相关。对于仅归因于与aza相关的副作用的辍学(n=16),与ITPA94C>A显著相关(P=0.002;OR=7.8;95%CI,2.1-29.1).24周研究期间的事件时间分析显示,退出时间与ITPA94C>A突变等位基因携带者状态之间存在显着关联(P=0.031)。
结论:ITPA94C>A突变或低TPMT活性的患者构成了从aza治疗中退出的药物遗传学高危人群。ITPA94C>A似乎是一个有希望的标记,表明容易出现氮杂不耐受。
BACKGROUND: Azathioprine (aza) therapy is beneficial in the treatment of inflammatory bowel disease, but 10%-30% of patients cannot tolerate aza therapy because of adverse drug reactions. Thiopurine S-methyltransferase (TPMT) deficiency predisposes to myelotoxicity, but its association with other side effects is less clear. Inosine triphosphatase (ITPA) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance.
METHODS: We analyzed data from a 6-month prospective
study including 71 patients with Crohn disease undergoing first-time aza treatment with respect to aza intolerance. Patients were genotyped for common TPMT and ITPA mutations and had pretherapy TPMT activity measured.
RESULTS: Early drop-out (within 2 weeks) from aza therapy was associated with ITPA 94C > A [P = 0.020; odds ratio (OR), 4.6; 95% confidence interval (95% CI), 1.2-17.4] and low TPMT activity [<10 nmol/(mL erythrocytes . h); P = 0.007; OR = 5.5; 95% CI, 1.6-19.2]. A high-risk group defined by ITPA 94C > A or TPMT <10 nmol/(mL erythrocytes . h) showed significant association with early drop-out (P = 0.001; OR = 11.3; 95% CI, 2.5-50.0) and all drop-outs (P = 0.002; OR = 4.8; 95% CI, 1.8-13.3). For only drop-outs attributable to aza-related side effects (n = 16), there was a significant association with ITPA 94C > A (P = 0.002; OR = 7.8; 95% CI, 2.1-29.1). Time-to-event analysis over the 24-week
study period revealed a significant association (P = 0.031) between the time to drop-out and ITPA 94C > A mutant allele carrier status.
CONCLUSIONS: Patients with ITPA 94C > A mutations or low TPMT activity constitute a pharmacogenetic high-risk group for drop-out from aza therapy. ITPA 94C>A appears to be a promising marker indicating predisposition to aza intolerance.