Pharmacogenetics of the Statin Response

他汀类药物反应的药物遗传学

• 批准号: 6805273
• 负责人: ERNST JOHN SCHAEFER
• 金额: $ 79.13万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-29 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805273
• 关键词: alleles; antihypercholesterolemic agent; apolipoproteins; cholesterol; clinical research; coronary disorder; gene frequency; genetic polymorphism; genotype; high density lipoproteins; human genetic material tag; lipid metabolism; naphthalenes; nucleic acid purification; nucleic acid sequence; pharmacogenetics; sitosterols; statistics /biometry; two dimensional gel electrophoresis

DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is the leading cause of death and disability in our society. Most CHD deaths occur in subjects over 70 years of age. Significant independent CHD risk factors are age, gender, elevated low density lipoprotein (LDL) cholesterol (C), decreased high density lipoprotein (HDL) C, hypertension, smoking, diabetes, elevated lipoprotein (a) or Lp(a) (LDL C> 50% reduction), and elevated C-reactive protein. In this response to RFA HL-03-001 (ancillary pharmacogenetic studies), we propose to study 2804 male and 3000 female participants in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), who were selected for age 70-82 years, having vascular disease coronary, cerebral or peripheral) or increased CHD risk due to smoking, hypertension or diabetes and total cholesterol levels between 4.0 and 9.0 mml/L or 151 and 340 mg/dl. In this randomized controlled trial pravastatin decreased LDL C 34% and triglyceride 12% and raised HDL C 5%. C-reactive protein and Lp(a) values have already been measured. Fatal and nonfatal myocardial infarction (MI) were decreased by 19%, and fatal MI 24%, but increased risk of new cancer were noted in the pravastatin group over 3.2 years as compared to the placebo group (all p<0.01) (Lancet 360: 1623-30, 2002). Benefit was greatest in subjects with low HDL C (<1.1 lmml/L or 43 mg/dl). No benefit of pravastatin versus placebo on cognitive function or stroke was noted. We and others have shown that statins increase large alpha 1 migrating apolipoprotein A-I containing HDL, decrease plasma lathosterol, a marker of cholesterol synthesis, and increase plasma betasitosterol, a marker of cholesterol absorption as well as decrease cholesterol ester transfer protein (CETP) mass. We propose to measure HDL subspecies, CETP mass, lathosterol, and beta-sitosterol in the 292 subjects who developed CHD while on pravastatin and in a control group (n=292) who did not develop CHD on pravastatin. We propose to isolate DNA in all subjects, carry out sequencing for single nucleotide polymorphism detection in 5 male and 5 female hyper-responders and the same number of hypo-responders (LDL C <10% reduction) and then genotyping at all SNPs on the two 292 patients groups, and the informative SNP detection on the entire 5804 cohort at the following gene loci: ATP binding cassette transporters G5 and G8 (ABCG5, ABCG8), CETP; HMG CoA reductase, apolipoprotein E, lipoprotein and hepatic lipase, microsomal transfer protein, C-reactive protein, connexin, plasminogen activator type I inhibitor and stromelysin I. These genes have been selected because of our own preliminary studies, and their known key role in cholesterol absorption and lipoprotein metabolism or CHD. We hypothesize that response to pravastatin in terms of lowering of LDL C, triglycerides and C-reactive protein, and HDL C raising will be related to specific genotypes and haplotypes. We also hypothesize that subjects with the greatest LDL C- and C-reactive protein-lowering, the greatest increase in large alpha HDL particles, the greatest reduction in lathosterol and the least increase in beta-sitosterol will have the greatest benefit in CHD risk reduction, and that these changes will be related to specific genotypes and haplotypes of the candidate genes being examined. These results can be used to formulate guidelines for identifying elderly subjects for statin treatment to prevent future CHD.

描述（由申请人提供）： 冠心病是导致人类死亡和残疾的主要原因。大多数CHD死亡发生在70岁以上的受试者中。显著的独立CHD风险因素是年龄、性别、升高的低密度脂蛋白（LDL）胆固醇（C）、降低的高密度脂蛋白（HDL）C、高血压、吸烟、糖尿病、升高的脂蛋白（a）或Lp（a）（LDL C降低> 50%）和升高的C-反应蛋白。在对RFA HL-03-001的回复中（辅助药物遗传学研究），我们计划在老年风险人群中进行普伐他汀前瞻性研究（PROSPER），研究对象为2804名男性和3000名女性，年龄70-82岁，患有冠状动脉、脑血管或外周血管疾病，或因吸烟而增加CHD风险，高血压或糖尿病和总胆固醇水平在4.0和9.0 mml/L或151和340 mg/dl之间。在随机对照试验中，普伐他汀降低LDL C 34%和甘油三酯12%，升高HDL C 5%。C-反应蛋白和Lp（a）值已经测量。与安慰剂组相比，普伐他汀组的致死性和非致死性心肌梗死（MI）降低了19%，致死性MI降低了24%，但在3.2年内观察到新发癌症的风险增加（所有p<0.01）（Lancet 360：1623-30，2002）。在低HDL C（<1.1 lmml/L或43 mg/dl）的受试者中获益最大。与安慰剂相比，普伐他汀对认知功能或卒中没有益处。我们和其他人已经表明，他汀类药物增加了含有HDL的大α 1迁移载脂蛋白A-I，降低了血浆胆固醇合成的标志物--脂甾醇，增加了血浆β-谷甾醇，胆固醇吸收的标志物，以及降低了胆固醇酯转移蛋白（CETP）的质量。我们建议测量292例在普伐他汀治疗期间发生CHD的受试者和对照组（n=292）中未发生CHD的受试者的HDL亚种、CETP质量、脂甾醇和β-谷甾醇。我们建议在所有受试者中分离DNA，在5名男性和5名女性高反应者和相同数量的低反应者中进行单核苷酸多态性检测测序（LDL C <10%降低），然后在两个292名患者组的所有SNP处进行基因分型，并在以下基因位点对整个5804队列进行信息性SNP检测：ATP结合盒转运蛋白G5和G8（ABCG 5、ABCG 8）、CETP; HMG CoA还原酶、载脂蛋白E、脂蛋白和肝脂肪酶、微粒体转移蛋白、C-反应蛋白、连接蛋白、纤溶酶原激活物I型抑制剂和基质溶解素I。这些基因被选择是因为我们自己的初步研究，以及它们在胆固醇吸收和脂蛋白代谢或CHD中已知的关键作用。我们推测普伐他汀降低LDL C、甘油三酯和C反应蛋白以及升高HDL C的作用与特定的基因型和单倍型有关。我们还假设，具有最大的LDL C-和C-反应蛋白降低、最大的大α HDL颗粒增加、最大的胆甾醇减少和最小的β-谷甾醇增加的受试者将在CHD风险降低方面具有最大的益处，并且这些变化将与正在检查的候选基因的特定基因型和单倍型相关。这些结果可用于制定指南，以确定老年受试者的他汀类药物治疗，以防止未来的冠心病。