Central Manchester & Manchester Children's University Hospitals NHS Trust, Manchester Royal Infirmary, Manchester, UK.
Pharmacogenomics. 2010 Feb;11(2):177-88. doi: 10.2217/pgs.09.155.
Thiopurine S-methyltransferase (TPMT) metabolizes thiopurine medications, including azathioprine and 6-mercaptopurine. Absent TPMT activity (i.e., in individuals homozygous for a variant TPMT allele) is associated with an increased risk of myelosuppression in patients taking thiopurine drugs. However, it is not clear if there is also an increased risk for patients with intermediate TPMT activity (i.e., in individuals heterozygous for a variant TPMT allele).
To quantify the increased risk of myelosuppression for patients with intermediate TPMT activity.
MATERIALS & METHODS: A systematic review identified published studies, up to 29 September 2008, that explored the relationship between TMPT and hematological adverse drug reactions to thiopurines. Following a critical appraisal of the quality of published studies, a meta-analysis calculated the odds ratio of myelosuppression for patients with intermediate TPMT activity compared with wild-type.
A total of 67 studies were identified, the majority retrospective cohort in design. Patients with two TPMT variant alleles who are TPMT deficient have a substantial increase in their risk of myelotoxicity (86% of deficient patients developed myelosuppression). The increase in odds ratio of developing leukopenia for patients with intermediate TPMT activity or one TPMT variant allele compared with wild-type was 4.19 (95% CI: 3.20-5.48).
This meta-analysis suggests that individuals with both intermediate and absent TPMT activity have an increased risk of developing thiopurine-induced myelosuppression, compared with individuals with normal activity. However, there is significant variability in the quality of the reported studies and large prospective studies to clarify the size of the effect of TPMT variant alleles on the risk of myelosuppression should be conducted. Accurate risk assessments will provide important data to inform clinical guidelines.
定量评估 TPMT 中间活性患者发生骨髓抑制的风险增加情况。
系统检索截至 2008 年 9 月 29 日公开发表的相关研究，评估 TPMT 与巯嘌呤类药物导致血液学不良反应之间的关系。对文献质量进行严格评价后，采用荟萃分析方法计算 TPMT 中间活性患者与野生型患者发生骨髓抑制的比值比。
共纳入 67 项研究，其中多数为回顾性队列设计。完全缺乏 TPMT 活性（携 2 个 TPMT 变异等位基因）的患者发生骨髓毒性的风险显著增加（86%的 TPMT 缺乏患者发生骨髓抑制）。与野生型患者相比，TPMT 中间活性或携 1 个 TPMT 变异等位基因的患者发生白细胞减少的比值比为 4.19（95%CI：3.20-5.48）。
本荟萃分析提示，与野生型患者相比，TPMT 中间活性和完全缺乏 TPMT 活性的个体发生巯嘌呤类药物诱导骨髓抑制的风险均增加。但是，纳入研究的质量存在较大差异，需要开展大型前瞻性研究以明确 TPMT 变异等位基因对骨髓抑制风险的影响程度。准确的风险评估可为临床指南的制定提供重要数据。
