中文摘要
心血管疾病是人类死亡的首要原因。中国官方数据显示中国有2亿3千万人患有心血管疾病。高脂血症是公认的心血管疾病的主要危险因素之一。他汀类药物是目前临床上最有效的降胆固醇药物，但他汀药物的药物代谢动力学，降低胆固醇和降低心血管事件的作用存在很大的个体差异。目前认为遗传因素对他汀药物反应的个体差异有重要作用。我们前期的研究证实遗传变异可影响他汀药物的安全性和降胆固醇的疗效。近年研究显示表观遗传修饰可影响药物的安全性和疗效。本课题首次研究与他汀药物代谢密切相关的基因（包括CYP450酶，药物转运蛋白以及核受体）的DNA甲基化和microRNA的表达对瑞舒伐他汀和辛伐他汀在386位华裔高胆固醇患者中血药浓度及降胆固醇作用的影响；并通过体外试验在人正常肝细胞及正常结肠上皮细胞中验证体内研究结果并探讨作用机制。本研究有望提高我们对如何更安全有效地使用他汀药物的认知，从而降低心血管事件在中国人群的发生。
英文摘要
Cardiovascular disease (CVD) is the number one cause of death globally. In China, official data indicates that about 230 million people have CVD with every 1 in 5 adults in China having CVD. Elevated plasma lipids are one of the key risk factors. Although statins are the cornerstone of lipid-lowering therapy to reduce the risk of CVD, there are wide variations in the lipid response and cardiovascular outcomes in statin users. It has been recognized that genetic factors play an important role in determining drug response. We and others have shown that genetic variations can influence the safety and the lipid-lowering effect of statins. It is becoming increasingly evident that in addition to the interindividual differences attributable to genetic polymorphisms, epigenetic modifications further generates interindividual differences in phenotype that may be of importance with respect to drug response. Epigenetic factors may have significant impact on to statins response, but this has not been investigated. This study will investigate DNA methylation and microRNA in drug metabolizing enzymes, drug transporters and nuclear receptors in determining the systemic exposure and lipid response to rosuvastatin and simvastatin in 386 Chinese patients with hypercholesterolaemia. We will then perform more definitive mechanistic investigation to verify if these epigenetic parameters will affect the expression and activity of genes related to the pharmacokinetics of statin in normal hepatic and colonic cell line models. This study would be the first pharmacoepigenetics of statin response and drug levels in a homogenous Chinese population and it holds great potential for identification of epigenetic biomarkers for the lipid-response to the two commonly used statins in Chinese patients with hypercholesterolaemia as well as epigenetic determinants of the plasma concentrations of statins. Pharmacoepigenetics of statins will help to improving our understanding how to use the drug more safely and efficiently and thus reduce the burden of CVD in Chinese population.
结题摘要
心血管疾病是人类死亡的首要原因。中国官方数据显示中国有2亿3千万人患有心血管疾病。高脂血症是公认的心血管疾病的主要危险因素之一。他汀类药物是目前临床上最有效的降胆固醇药物，但他汀药物的药物代谢动力学，降低胆固醇和降低心血管事件的作用存在很大的个体差异。目前认为遗传因素对他汀药物反应的个体差异有重要作用。我们前期的研究证实遗传变异可影响他汀药物的安全性和降胆固醇的疗效。近年研究显示表观遗传修饰可影响药物的安全性和疗效。本课题首次研究与他汀药物代谢密切相关的基因（包括CYP450酶，药物转运蛋白以及核受体）的DNA甲基化和microRNA的表达对瑞舒伐他汀和辛伐他汀在386位华裔高胆固醇患者中血药浓度及降胆固醇作用的影响；并通过体外试验在人正常肝细胞及正常结肠上皮细胞中验证体内研究结果并探讨作用机制。本研究有望提高我们对如何更安全有效地使用他汀药物的认知，从而降低心血管事件在中国人群的发生。研究者按照研究方案积极开展了此研究，对靶基因进行了筛选、对靶基因引物的进行了设计、对DNA样本进行了预处理并开展了DNA 甲基化实验、并对PCR试验条件进行了摸索与优化。但是由于主要研究者离职，而新的工作单位不是国家自然科学基金依托单位，无法作为项目负责人执行此项目, 故而在2016年底申请终止项目的实施。并已将研究经费返还给基金单位。