华法林个体化治疗表观遗传药理学标志物筛选及临床应用

Warfarin, as a eutherapeutic and cheap oral anticoagulant that used widely around the world since 1950s, is not being used in China commonly due to its narrow therapeutic index, wide inter-individual variability in dose requirement and severe ADR. Due to the severe ADR such as thrombosis and bleeding after dosing, the usage of this anticoagulant is limited. Enhancing the usage of warfarin in thromboembolic disease to fulfill the international guideline through improving the medication safety while decreasing the ADR risk of warfarin should be a major concern in the field of anticoagulant research. Pharmacogenetics research has proved that genetic variation is the major factor that affects warfarin dose requirement. To date, many genotype-guided dosing algorithms have been established from different studies, including the most widely used International Warfarin Pharmacogenetics Consurtium (IWPC) algorithm. Most of them are only capable to explain 50-70% of the variations in warfarin dosing. But these algorithms are still not accuracy enough, which caused the personalized therapy of warfarin is not as effective as expected. As have been proved by many empirical articles, epigenetic is a critical factor which can affect medicine reactivity, we believed that epigenetic research in warfarin dosage adaption is more important. In the other hand, the time used to achieve a stable INR based on pharmacogenetics algorithm cannot be significantly differed from traditional clinical algorithm. These results indicate that genotype is not the only factor which affects warfarin dosing. Epigenetic factor may also plays an important role in warfarin metabolism. Our group has previously finished the primary screening for miRNAs targeting warfarin metabolism pathway key genes and methylation status which may be related to different warfarin reactive status. We have identified 22 miRNAs and 71 methylation variations gene that may affect the metabolism efficiency of warfarin. We are continuing to screen and verify useful epigenetic markers for warfarin personalized therapy by using bioinformatics and microarray technique. Testing methods for new gene-markers and improved dosing algorithm will be established as soon as they got verified and confirmed. The estimated goal of this research is to improve warfarin dosing efficiency based on newly developed gene-markers and dosing algorithm. Although our research is mostly focusing on warfarin epigenetic, it can also be a valuable reference for researchers who are working on pharmacoepigenetics for any other medicine.

华法林是疗效明确且价廉的经典口服抗凝药，但因个体剂量差异大、治疗窗窄，易产生出血和血栓副作用，致其使用率低。如何提高华法林疗效与安全性，进而提高其使用率，是临床抗凝治疗急需解决的重要问题。华法林剂量差异已明确主要由基因所致，国内外学者已建立多个基因型剂量预测模型。但是这些模型准确率尚不够高，疗效和安全性优势仍不明显。因此，研究影响华法林反应性的基因型外遗传因素更显迫切。表观遗传药理学是个体化治疗研究新热点。课题组前期进行华法林代谢通路关键基因的miRNA和不同华法林反应性患者差异甲基化位点的初筛，获得了22个重要miRNA和71个甲基化差异基因，拟继续利用生物信息学和基因芯片技术筛选并验证与华法林剂量相关的表观遗传药理学标志物，建立适宜的检测方法和多因素剂量预测模型以提高个体预测准确率，达到提高华法林个体化治疗效果的目标。本研究也将为其他药物的表观遗传药理学标志物研究提供基础和参考。

华法林是疗效明确且价廉的经典口服抗凝药，但因个体剂量差异大、治疗窗窄，易产生出血和血栓副作用，致其使用率低。如何提高华法林疗效与安全性，进而提高其使用率，是临床抗凝治疗急需解决的重要问题。华法林剂量差异已明确主要由基因所致，国内外学者已建立多个基因型剂量预测模型。但是这些模型准确率尚不够高，疗效和安全性优势仍不明显。因此，研究影响华法林反应性的基因型外遗传因素更显迫切。表观遗传药理学是个体化治疗研究新热点。课题组通过完善华法林个体化治疗分子诊断研究样本库、筛选和验证华法林个体剂量相关的DNA甲基化位点、筛选和验证华法林个体剂量相关的血浆microRNA，建立了一套表观遗传药理学标志物研究的方法，补充了华法林表观遗传药理学的DNA甲基化和microRNA研究数据，有望将这些标志物用于指导华法林个体化治疗，项目共发表SCI论文4篇、北大核心期刊论文1篇、获授权专利4项，培养3名博士和1名硕士生。