Pharmacogenetics of the Statin Response

描述(由申请人提供)： 冠心病(CHD)是当今社会导致死亡和残疾的主要原因。大多数冠心病死亡发生在70岁以上的受试者中。显著的独立冠心病危险因素有年龄、性别、低密度脂蛋白(LDL)胆固醇(C)升高、高密度脂蛋白(HDLc)降低、高血压、吸烟、糖尿病、Lp(A)或Lp(A)升高(低密度脂蛋白降低50%)和C反应蛋白升高。为了响应RFA HL-03-001(辅助药物遗传学研究)，我们建议对2 804名男性和3 000名女性进行普伐他汀在高危老年人(PROSPER)中的前瞻性研究，这些患者年龄在70-82岁之间，患有心血管疾病(冠心病、脑血管疾病或外周疾病)或因吸烟、高血压或糖尿病而增加冠心病风险，总胆固醇水平在4.0至9.0mml/L或151至340 mg/dl之间。在这项随机对照试验中，普伐他汀降低低密度脂蛋白胆固醇34%，甘油三酯12%，升高高密度脂蛋白胆固醇5%。已经测量了C反应蛋白和Lp(A)的值。与安慰剂组相比，服用普伐他汀3.2年后，致命性和非致命性心肌梗死(MI)减少了19%，致命性MI减少了24%，但新癌症的风险增加(均P&lt；0.01)(《柳叶刀》360：1623-30,2002)。低高密度脂蛋白胆固醇(1.1mml/L或43 mg/dl)的受试者受益最大。普伐他汀与安慰剂相比在认知功能或中风方面没有好处。我们和其他人已经证明，他汀类药物增加了含有高密度脂蛋白的大量α1迁移性载脂蛋白A-I，降低了血浆胆固醇合成的标记物Lathosterol，增加了胆固醇吸收的标记物Betasitosterol，并减少了胆固醇酯转移蛋白(CETP)的质量。我们建议测量292例服用普伐他汀期间发生冠心病的受试者和292例未服用普伐他汀的对照组(n=292)的高密度脂蛋白亚型、CETP质量、催乳素和β-谷甾醇。我们建议分离所有受试者的DNA，对5名男性和5名女性高反应者和相同数量的低反应者(低密度脂蛋白C&lt；减少10%)进行单核苷酸多态检测，然后对这两个292名患者组的所有SNP进行基因分型，并在以下基因座对整个5804个队列进行信息SNP检测：ATP结合盒转运体G5和G8(ABCG5，ABCG8)，CETP；HMG辅酶A还原酶、载脂蛋白E、脂蛋白和肝脂酶、微粒体转运蛋白、C反应蛋白、连接蛋白、纤溶酶原激活物I抑制物和基质分解蛋白I。这些基因的选择是基于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(CHD)中的关键作用。我们假设普伐他汀在降低低密度脂蛋白、甘油三酯和C反应蛋白方面的反应，以及升高高密度脂蛋白胆固醇将与特定的基因和单倍型有关。我们还假设，低密度脂蛋白和C反应蛋白降幅最大、大的α-高密度脂蛋白颗粒增加最多、Lathosterol减少最多、β-谷甾醇增加最少的受试者将在降低CHD风险方面受益最大，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有关。这些结果可用于制定指南，以确定接受他汀类药物治疗的老年受试者，以预防未来的冠心病。

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.