中国人群奥氮平药物反应相关遗传学及表观遗传学标记的综合性研究

Olanzapine is a widely used drug for schizophrenia treatment. Clinical practice demonstrated its efficacy varies greatly among individuals and may lead to adverse drug reactions in some cases, which can cause great treatment costs and injury to patients. The most important solution for this problem is accurate identification of drug-response-related pharmacogenomic markers to enable personalized medicine. Considering drug reaction is multi-factor complex traits, in this study we plan to overcome the weaknesses in previous studies such as the small sample sizes, limitation to fewer gene analysis and lack of functional and clinical verification. Then we will carry out genetic and epigenetic studies of olanzapine metabolizing, transporter and drug target genes by large sample size and multi-gene systematic analysis based on our recently founded polymorphism database of drug metabolizing enzyme genes and other related genes in Chinese population. So, we can comprehensively identify the drug-response-related markers and their combinations of olanzapine in Chinese population. Through following functional and clinical verification, we can find the correct and valid drug-response-related markers and their combinations. According to the results of above study, we will develop the mathematics model for optimum dose predicting of olanzapine for Chinese population. Also, we will develop the guidance system for personalized medicine of olanzapine. This study could lay a solid foundation for the realization of olanzapine personalized medicine in Chinese population in the future.

奥氮平是精神分裂症治疗中广泛应用的药物之一，临床实践显示其药效个体差异较大，同时会产生一系列不良反应，给患者带来了巨大的医疗耗费及危害。寻找其药物反应相关的最精确地药物基因组学标记推行个性化用药是解决这一问题的重要途径。药物反应是涉及多因素的复杂性状，本课题中我们克服以往相关研究局限于小样本量、个别基因及因素且缺乏功能及临床验证的缺陷，在最近我们建立的中国人群药物代谢酶等相关基因多态性数据库的基础上，从遗传学及表观遗传学两个方面，对奥氮平药物代谢酶基因、药物转运体基因及作用靶点基因进行药物反应相关的大样本量多基因系统性分析，从而较全面的确定中国人群奥氮平药物反应相关标记及其组合，并随后将之进行功能及临床验证，筛选出准确有效的药物反应标记及组合。基于此设计出中国人群奥氮平最适剂量预测数学模型并初步建立其个性化用药指导体系。为将来实现中国人群奥氮平的个性化用药奠定基础。

奥氮平是临床上精神分裂症治疗广泛应用的药物之一，其药效个体差异给患者带来了巨大的医疗耗费及危害。为了寻找其药物反应相关的最精确地药物基因组学标记并进而推行个性化用药，本课题中我们在最近我们建立的中国人群药物代谢酶等相关基因多态性数据库的基础上，通过综合应用遗传学分析方法首先完成了多个CYP基因联合基因型分析和联合表型分析，开展了奥氮平重要药物代谢酶CYP2D6基因调控区及编码区基因变异的功能机制研究，建立了R441H（T4046C）等20多个基因变异位点及其组合的表现型数据库。在收集的奥氮平药物反应相关样本中，采用二代测序技术对奥氮平药物代谢酶基因、药物转运体基因及作用靶点基因等147个基因进行了药物反应相关的大样本量多基因系统性分析，并随后将之进行了较大样本量的重复验证，最终发现了DRD3等10个准确有效的中国人群奥氮平药物反应相关标记及其组合。同时本课题开展了奥氮平药物反应相关甲基化及Micro RNA表观遗传学分子标记研究，发现了CYP3A4表达调控相关的Hsa-miR-27a等表观遗传学标记。最后我们在综合评价前期所发现的奥氮平药物反应相关分子标记物的基础上结合临床参数初步建立了其个性化用药指导体系。为将来实现中国人群奥氮平的个性化用药奠定了基础。