Discovering lipoprotein lipase pathway variants that protect against CHD

项目摘要和摘要 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 疾病(CHD)，仍然是一个重大的残余风险。这一观察提出了以下基本问题： 除了低密度脂蛋白-C，哪种脂质途径(S)影响人类患冠心病的风险？我们收集到了初步证据 表明脂蛋白脂酶(LPL)途径在人类CHD的发生发展中起重要作用。常见的， 脂蛋白脂肪酶(LPL)和编码LPL的两个基因的低频率和/或罕见的DNA序列变异- 调节蛋白(APOA5、APOC3)不仅与血浆甘油三酯(TG)有关，而且与CHD的风险有关。为 例如，通过外显子组测序，我们发现每150个人中就有1人携带四种罕见的 载脂蛋白C-III(APOC3)突变，每个突变导致功能丧失(LoF)(Crosby*，Peloso*，N Engl J 医学，在印刷中)。载脂蛋白C3LoF突变携带者血浆甘油三酯和载脂蛋白III水平较低， 患冠心病的风险降低40%(P=4x10-6)。这些发现表明，除了低密度脂蛋白-C，LPL途径是一个关键 并提出了几个问题：(1)调节LPL/与LPL相互作用的全套基因是什么 并构成LPL途径？；(2)LPL途径中是否还有其他基因具有罕见的心脏保护作用 等位基因？；以及(3)我们能否研究载脂蛋白C3保护性等位基因携带者的生理学以了解机制 在防御工事后面？针对这些问题，我们提出了以下具体目标： 目的1：检验LPL途径中的额外基因可以通过计算发现的假设 这些新基因的途径和编码变异将与血浆甘油三酯相关； 目的2：验证LPL途径基因(APOC3以外)含有罕见的LOF等位基因保护的假说 抗冠心病；以及 目的3：验证载脂蛋白C3LoF突变携带者增加富含甘油三酯的脂解作用的假设 脂蛋白和改善的胰岛素敏感性。 此外，国际和平协会还组建了一个指导委员会，该委员会将提供必要的培训和支助。 以完成拟议的研究，并促进PI的发展。拟议的研究将训练 一名年轻的调查员在三个关键领域：(1)。扩大她对脂蛋白代谢的了解；发展，发展 执行和解释路径分析的技能；以及(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会推动 作为一名生物医学调查员，PI走向了独立。

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.