Discovering lipoprotein lipase pathway variants that protect against CHD

发现预防冠心病的脂蛋白脂肪酶途径变体

• 批准号: 8804634
• 负责人: Gina Marie Peloso
• 金额: $ 13.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804634
• 关键词: Address; Affect; Algorithms; Alleles; Apolipoproteins C; Area; Attenuated; Biological Assay; Blood Glucose; Cell Culture Techniques; Code; Consent; Coronary heart disease; DNA Sequence; Data; Data Analyses; Data Set; Databases; Development; Disease; Enzymes; Fatty acid glycerol esters; Frequencies; Future; Genes; Genetic Variation; Genotype; Growth; Healthcare; Heparin; Hepatic; Hour; Human; Human Genetics; Individual; Insulin Resistance; Knowledge; LDL Cholesterol Lipoproteins; Lipids; Lipolysis; Lipoproteins; Measurement; Mentors; Metabolism; Mining; Modeling; Mus; Mutation; OGTT; Oral; Participant; Pathway Analysis; Pathway interactions; Penetrance; Phenotype; Physiology; Plasma; Proteins; Recruitment Activity; Research; Research Personnel; Residual state; Risk; Route; Seeds; Testing; Time; Training; Training Support; Triglycerides; Variant; apolipoprotein C-III; base; biobank; case control; design; exome; exome sequencing; genetic analysis; heart disease risk; improved; insulin sensitivity; interest; lipoprotein lipase; loss of function; loss of function mutation; metabolic abnormality assessment; mutation carrier; novel; protein protein interaction; public health relevance; rare variant; research study; skills

 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.

 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）可降低冠心病（CHD）风险，但仍存在显著的剩余风险。这一观察结果提出了以下基本问题：除了LDL-C，哪种脂质途径影响人类CHD的风险？我们已经积累了初步证据，表明脂蛋白脂肪酶（LPL）途径有助于人类CHD的发展。脂蛋白脂酶（LPL）和两种编码LPL调节蛋白（APOA 5，APOC 3）的基因中常见，低频和/或罕见的DNA序列变异与CHD风险以及血浆甘油三酯（TG）相关。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）突变之一，每种突变都导致功能丧失（LoF）（克罗斯比 *，Peloso*，N Engl J Med，出版中）。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CHD的关键途径，并提出了几个问题：（1）什么是调控LPL/与LPL相互作用并构成LPL途径的全套基因？(2)在LPL途径中是否有其他基因具有罕见的心脏保护等位基因？以及（3）我们是否可以研究APOC 3保护性等位基因携带者的生理学，以了解保护背后的机制？为了解决这些问题，我们提出了以下具体目标：目的1：验证LPL途径中的其他基因可以使用计算方法发现并且这些新基因中的编码变异将与血浆TG相关的假设;目的2：验证LPL途径基因与血浆TG相关的假设。目的3：检验AP 0 C3 LoF突变携带者具有增加的富含TG的脂蛋白的脂解和改善的胰岛素敏感性的假设。此外，PI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持，以完成拟议的研究，并促进PI的成长。这项研究将在3个关键领域培养一名年轻的研究人员：（1）。扩大对脂蛋白代谢的认识;（2）。培养进行和解释途径分析的技能;（3）进行假设驱动的人体生理学实验。成功完成培训计划和拟议的研究应推动PI成为独立的生物医学研究者。