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（CHD）是我们社会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。重要的独立CHD危险因素是年龄，性别，低密度脂蛋白（LDL）胆固醇（C）升高，降低了高密度脂蛋白（HDL）C，高血压，吸烟，糖尿病，脂蛋白升高（A）或LP（A）或LP（A）或LDL C> 50％降低C> 50％降低C蛋白蛋白。在对RFA HL-03-001（辅助药物遗传学研究）的这种反应中，我们建议研究2804名男性和3000名女性参与者，用于对pravastatin的前瞻性研究（PROSPER）的前瞻性研究，他们被选择为70-82岁，患有70-82岁的parcular疾病，脑部或糖尿病的风险，或者伴有脑部或糖尿病的风险）在4.0至9.0 mml/L或151和340 mg/dl之间。在这项随机对照试验中，pravastatin降低了LDL C 34％和甘油三酸酯12％，并提高了HDL C 5％。 C反应蛋白和LP（A）值已经测量。致命和非致命性心肌梗塞（MI）降低了19％，致命的MI 24％，但与安慰剂组相比，Pravastatin组的新癌症风险增加了3.2年（所有P <0.01）（lancet 360：1623-30，2002，2002，2002）。在低HDL C（<1.1 LMML/L或43 mg/dL）的受试者中，益处最大。没有注意到pravastatin与安慰剂对认知功能或中风的好处。我们和其他人表明，他汀类药物增加了大α1迁移载脂蛋白A-I含有HDL，减少血浆late骨固醇，胆固醇合成的标志物，并增加血浆βββ蛋白蛋白蛋白酚，胆固醇吸收的标志物以及减少胆固醇酯转移蛋白（CETP）的质量。我们建议在292名受试者中测量HDL亚种，CETP质量，laterosterlol和β-位乙醇固醇，这些受试者在pravastatin和对照组（n = 292）中开发CHD的受试者（n = 292），他们没有在pravastatin上开发CHD。 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 CETP转运蛋白G5和G8（ABCG5，ABCG8）； 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，纤溶酶原激活剂I型抑制剂和Stromelysin I.之所以选择这些基因。这些基因已被选择，因为我们自己的初步研究，以及它们在胆固醇吸收术中的主要研究和胆固醇的作用。我们假设在降低LDL C，甘油三酸酯和C反应蛋白以及HDL C升高的情况下，对Pravastatin的反应将与特定的基因型和单倍型有关。 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.这些结果可用于制定指南，以识别他汀类药物治疗的老年受试者，以防止未来的冠心病。