NUTD15遗传和表观水平变异与硫代嘌呤不良反应的相关性和机制研究

药物不良反应已成为重要的全球性公共医疗问题。硫代嘌呤引起的骨髓抑制是临床上常见的严重药物不良反应。在欧美人群中发现TPMT基因上存在相关遗传位点，但并不适用于东亚人。最近研究在NUDT15基因上发现一个东亚人群中高频变异的位点，可解释大部分硫代嘌呤引起的骨髓抑制。考虑还存在已知位点无法解释的患者，我们前期对188例儿童急性淋巴白血病患者进行NUDT15变异研究，验证了已知位点与药物性骨髓抑制的相关性，并找到了可提高预测敏感性的其它位点。因此提出假设：NUDT15其它位点变异、表观遗传改变或肠道菌群变化可能影响硫代嘌呤引起的骨髓抑制。我们拟在更大样本中研究NUTD15变异，以期找到更多相关的遗传位点。同时在临床样本，细胞和敲除小鼠模型中利用表达测定、酶活分析、药敏实验、菌群测序等手段确定这些因素影响药物性骨髓抑制的机制。该研究将为临床上硫代嘌呤药物用药方案提供更精准的指导。

Adverse drug reactions are considered as the public health problem globally. Thiopurine-induced Myelosuppressions are serious adverse drug reactions. A related variant has been discovered on TPMT gene based on European and American populations, but it is incapable for predicting thiopurine-induced myelosuppression in East Asians. Recent study has found a variant on NUDT15. The variant shows a high frequency in East Asians and could explain the majority of thiopurine-induced myelosuppression. Considering those patients whose thiopurine-induced myelosuppression could not be predicted with the known variant, we have studied variants on NUDT15 in 188 children with acute lymphoblastic leukemia. Not only the investigation has validated the correlation between known variants and thiopurine-induced myelosuppression, but also found 3 novel variants which could improve sensitivity of the prediction. Therefore, we raise the hypothesis that other variants on NUDT15, epigenetic alterations, or changes in intestinal flora may affect thiopurine-induced myelosuppression. We plan to study NUTD15 variants in a larger-size cohort and try to find more pharmacological variants. Furthermore, we will perform expression assay, enzyme activity assay, drug sensitivity test, and bacterial sequencing in clinical samples, cell lines or knockout mouse models, and figure out how those factors affect drug-induced myelosuppression. The study will provide more precise guidance for thiopurine admission in clinical.