Discovering lipoprotein lipase pathway variants that protect against CHD

 描述(由申请人提供)：尽管他汀类药物治疗低密度脂蛋白胆固醇(LDL-C)降低了冠心病(CHD)的风险，但仍存在显著的残余风险。脂蛋白脂酶(LPL)和两个编码LPL调节蛋白的基因(APOA5、APOC3)中常见的、低频的和/或罕见的DNA序列变异与冠心病和血浆甘油三酯(TG)的风险有关。例如，通过外显子组测序，我们发现每150人中就有1人携带四种罕见的载脂蛋白C-III(APOC3)突变之一，每一种突变都会导致功能丧失(LoF)(Crosby*，Peloso*，N Engl J Med，in Press)。APOC3LoF突变携带者的血浆TG和apoC-III蛋白水平较低，冠心病风险降低40%(P=4×10-6)。这些发现表明，除了低密度脂蛋白-C，LPL途径是CHD的关键途径，并提出了几个问题：(1)调节LPL途径/与LPL途径相互作用的全套基因是什么？(2)LPL途径中是否还有其他基因具有稀有的心脏保护等位基因？以及(3)我们能否研究APOC3保护等位基因携带者的生理学，以了解保护机制？为了解决这些问题，我们提出了以下具体目标：目的1：检验假设可以通过计算方法发现LPL途径中的额外基因，并且这些新基因中的编码变异将与血浆TG相关；目标2：检验LPL途径基因(除APOC3以外)含有罕见的LOF等位基因以预防CHD的假设；以及目标3：检验APOC3 LOF突变携带者增加富含TG的脂蛋白的脂解并改善胰岛素敏感性的假设。此外，国际和平协会已成立了一个指导委员会，该委员会将提供必要的培训和支持，以完成拟议的研究，并促进国际和平协会的发展。拟议的研究将在三个关键领域培训一名年轻的调查员：(1)。扩大她对脂蛋白代谢的了解；

 DESCRIPTION (provided by applicant): 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.