Discovering lipoprotein lipase pathway variants that protect against CHD

项目概要和摘要 而他汀类药物治疗低密度脂蛋白胆固醇（LDL-C）可降低冠心病风险 冠心病（CHD），仍然存在显著的剩余风险。这一意见提出了以下基本问题： 除LDL-C外，哪种脂质途径影响人类CHD风险？我们收集了初步证据 显示脂蛋白脂酶（LPL）途径有助于人类CHD的发展。常见的， 脂蛋白脂酶（LPL）中的低频率和/或罕见DNA序列变体和编码LPL的两个基因， 调节蛋白（APOA 5，APOC 3）与CHD的风险以及血浆甘油三酯（TG）相关。为 例如，通过外显子组测序，我们发现150个个体中有1个携带四种罕见的 载脂蛋白C-III（APOC 3）突变，每种突变导致功能丧失（LoF）（克罗斯比 *，Peloso*，N Engl J Med，in press）. APOC 3 LoF突变携带者血浆TG和apoC-III蛋白水平较低， CHD风险降低40%（P = 4 x 10-6）。这些发现表明，除了LDL-C，LPL途径是一个关键， 冠心病的途径，并提出几个问题：（1）什么是全套基因调控/相互作用与LPL 并包含LPL途径？(2)LPL通路中是否有其他基因具有罕见的心脏保护作用， 等位基因？以及（3）我们能否研究APOC 3保护性等位基因携带者的生理学以了解其机制 保护的背后？为解决这些问题，我们提出以下具体目标： 目的1：验证LPL途径中的其他基因可以使用计算的方法发现的假设。 这些新基因的表达途径和编码变异与血浆TG水平相关; 目的2：验证LPL途径基因（除APOC 3外）含有罕见的LoF等位基因的假设， 预防冠心病;及 目的3：验证APOC 3 LoF突变携带者具有增加的富含TG的脂肪分解的假设。 脂蛋白和改善胰岛素敏感性。 此外，PI还组建了一个指导委员会，将提供必要的培训和支持 以完成拟议的研究，以及促进PI的增长。这项研究将训练 一个年轻的研究员在3个关键领域：（1）。扩大对脂蛋白代谢的认识;（2）。发展 执行和解释途径分析的技能;（3）执行假设驱动的人类 生理学实验成功完成培训计划和拟议的研究应推动 作为一名生物医学研究者独立的PI。

Project Summary and Abstract Whereas treatment of low-density lipoprotein cholesterol (LDL-C) with statins reduces risk for coronary heart disease (CHD), a significant residual risk remains. This observation raises the following fundamental question: beyond LDL-C, which lipid pathway(s) affects risk for CHD in humans? We have accrued preliminary evidence showing that the lipoprotein lipase (LPL) pathway contributes to the development of CHD in humans. Common, low-frequency, and/or rare DNA sequence variants in lipoprotein lipase (LPL) and two genes encoding LPL- regulating proteins (APOA5, APOC3) are associated with risk of CHD as well as plasma triglycerides (TG). For example, through exome sequencing, we discovered that 1 in 150 individuals carried one of four rare apolipoprotein C-III (APOC3) mutations, each leading to loss-of-function (LoF) (Crosby*, Peloso*, N Engl J Med, in press). Carriers of APOC3 LoF mutations had lower plasma TG and apoC-III protein level as well as 40% lower risk for CHD (P = 4 x 10-6). These findings indicate that beyond LDL-C, the LPL pathway is a key route to CHD and suggest several questions: (1) what is the full suite of genes that regulate/interact with LPL and comprise the LPL pathway?; (2) are there other genes in the LPL pathway with rare, cardio-protective alleles?; and (3) can we study physiology in APOC3 protective allele carriers to understand mechanisms behind the protection? To address these questions, we propose the following specific aims: Aim 1: To test the hypothesis that additional genes in the LPL pathway can be discovered using computational approaches and coding variation in these new genes will associate with plasma TG; Aim 2: To test the hypothesis that LPL pathway genes (beyond APOC3) harbor rare, LoF alleles that protect against CHD; and Aim 3: To test the hypothesis that APOC3 LoF mutation carriers have increased lipolysis of TG-rich lipoproteins and improved insulin sensitivity. Furthermore, the PI has assembled a mentoring committee who will provide the necessary training and support to accomplish the proposed research, as well as facilitate the growth of the PI. The proposed research will train a young investigator in 3 key areas: (1). To expand her knowledge of lipoprotein metabolism; (2). To develop skills for performing and interpreting pathway analysis; and (3) To perform hypothesis-driven human physiology experiments. Successful completion of the training plan and the proposed research should propel the PI to independence as a biomedical investigator.