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Deep phenotyping of ANGPTL3, ANGPTL4 and ANGPTL8 human knockouts and population based studies

ANGPTL3、ANGPTL4 和 ANGPTL8 人类基因敲除的深度表型分析和基于人群的研究

基本信息

批准号：
10528964
负责人：
Daniel James Rader
金额：
$ 61.94万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528964
关键词：
ANGPTL3 gene ANGPTL4 gene Address Animal Model Antisense Oligonucleotides Apolipoprotein A-I Apolipoproteins A Apolipoproteins B Biological Biology Cardiometabolic Disease Catabolism Consanguinity Coronary heart disease Data Development Disease Dose Enrollment Etiology Family Fasting Fatty acid glycerol esters Genes Genetic Genomics Genotype Hepatic Heterozygote High Density Lipoproteins Human Individual Isotopes Italy Kinetics Knock-out Knowledge LDL Cholesterol Lipoproteins Lipoproteins Low-Density Lipoproteins Measures Mediating Mediation Mendelian randomization Mesentery Metabolic Metabolic Clearance Rate Metabolism Monoclonal Antibodies Mutation Non-Insulin-Dependent Diabetes Mellitus OGTT Oral Pakistan Participant Pathway interactions Phenocopy Phenotype Plasma Population Group Population Study Production Proteins Resources Risk Risk Factors Risk Reduction Safety Serum Testing Therapeutic Triglycerides Uncertainty Variant Very low density lipoprotein X-Ray Computed Tomography abdominal CT base case control cohort gain of function mutation gene discovery glucose tolerance heart disease risk human model improved lipid metabolism liver function loss of function loss of function mutation lymphadenopathy particle population based response therapeutic target vascular risk factor

项目摘要

Several recent studies indicate that loss of function (LoF) mutations in the ANGPTL3, 4 and 8 gene lower levels of triglyceride rich lipoproteins (TRLs) and ANGPTL3 and ANGPTL4 LoF variants offer protection from coronary heart disease (CHD). Inhibition of the ANGPTL3, 4 or 8 can therefore provide an attractive therapeutic mechanism to lower CHD risk. There are however many outstanding uncertainties that exist, pertaining to the impact of complete or partial genetic deficiency of these three proteins on: (i) the relative contribution of TRL vs LDL vs HDL in mediating CHD risk reduction; (ii) the impact on the range of apoB and apoA containing lipoproteins; (iii) the interrelationships of these three ANGPTL proteins; (iv) the dose-response relationship with CHD risk; (v) the relevance of complete or partial deficiency to glucose tolerance; and (vi) the safety implications. This proposal aims to address these gaps by leveraging natural human models of ANGPTL3, 4 and 8 deficiency, already enrolled in two population groups: (i) an Italian cohort (n = 613) that is enriched for ANGPTL3 human knockouts (n = 22); (ii) the Pakistan Genomic Resource (PGR) (n ~ 100,000) enriched for consanguinity. Specifically, in AIM-1, in 22 trios (22 ANGPTL3 null homozygous knockouts and an equal number of heterozygotes and non-carriers) from Italy, we will measure: lipoprotein particle concentration, size, and composition, relationship with ANGPTL8 and ANGPTL4 levels in fed and fasting states, metabolic parameters (e.g., oral glucose tolerance test [OGTT]), and liver function. We will also evaluate the impact of ANGPTL3 deficiency on kinetics of apoB containing lipoproteins, including VLDL apoB production rate, conversion rates of VLDL to IDL and LDL apoB, and clearance rates of VLDL, IDL, and LDL apoB. We will also assess disease mediation by using ANGPTL3 LoF genotypes and CHD risk with LDL-C, TRL and other risk factors (n = 613). In AIM-2, will leverage the Pakistani bioresource, PGR, and in 22 ANGPTL4 LoF carriers and 22 non- carriers, we will measure: lipoprotein particle concentration, size, and composition, metabolic parameters (e.g., [OGTT]), and liver function. We will also assess kinetics of TRL-apoB and HDL apoA-I containing lipoproteins through isotope traced based studies and conduct OGTT, hepatic fat quantification and abdominal CT scans to test for lymphadenopathy. We will also conduct analyses to explore relative contribution of TG, LDL-C and HDL-C in mediating CHD risk conferred by ANGPTL4 LoF through large population based studies. In AIM-3, we will measure plasma ANGPTL8 in 5,000 incident MI cases and 5,000 controls, which will enable (a) MI case-control analyses, (b) gene-discovery analyses in relation to ANGPTL8 levels, and (c) Mendelian Randomization analyses to assess causality of ANGPTL8 levels with CHD risk. In 22 ANGPTL8 LoF carriers and 22 non-carriers, we will measure OGTT and hepatic fat to assess safety profile and conduct lipoprotein kinetic studies to examine the relationship of ANGPTL8 LoF with lipid metabolism.

最近的一些研究表明，Angptl3、4和8基因的功能丧失突变会降低富含甘油三酯的脂蛋白(TRL)和Angptl3和ANGPTL4 LoF变体的水平可提供保护冠心病(CHD)。因此，抑制Angptl3、4或8可以提供一种有吸引力的治疗方法降低冠心病风险的机制。然而，存在许多悬而未决的不确定性，与这三种蛋白质完全或部分遗传缺陷对：(I)TRL与低密度脂蛋白与高密度脂蛋白在降低冠心病风险中的比较；(Ii)载脂蛋白B和载脂蛋白A对载脂蛋白B和载脂蛋白A的影响脂蛋白；(Iii)这三种ANGPTL蛋白的相互关系；(Iv)与风险；(V)完全或部分缺乏与糖耐量的相关性；以及(Vi)安全性影响。这项提议旨在通过利用Angptl3、4和8的自然人类模型来解决这些差距缺乏症，已经登记在两个人群中：(1)意大利队列(n=613)，其Angptl3基因丰富人类基因敲除(n=22)；(Ii)巴基斯坦基因组资源(PGR)(n~100,000)，具有丰富的血缘关系。具体地说，在AIM-1中，在22个三联体中(22个Angptl3无效纯合子敲除和相等数量的杂合子和非携带者)，我们将测量：脂蛋白颗粒浓度、大小和摄食和禁食状态下ANGPTL8和ANGPTL4的组成及其与代谢参数的关系 (例如，口服葡萄糖耐量试验[OGTT])和肝功能。我们还将评估Angptl3的影响载脂蛋白的动力学缺陷，包括极低密度脂蛋白的生成率、转化率极低密度脂蛋白与低密度脂蛋白和低密度脂蛋白载脂蛋白B的比值，以及极低密度脂蛋白、低密度脂蛋白和低密度脂蛋白载脂蛋白B的清除率。我们还将评估疾病用Angptl3LoF基因型别和冠心病风险与低密度脂蛋白胆固醇、TRL和其他危险因素进行中介(n=613)。在AIM-2中，将利用巴基斯坦的生物资源PGR，并在22个ANGPTL4 LoF载体和22个非载体，我们将测量：脂蛋白颗粒浓度、大小和组成、代谢参数(例如， [OGTT])和肝功能。我们还将评估含有脂蛋白的TRL-apoB和HDLapoA-I的动力学通过基于同位素的研究并进行OGTT、肝脏脂肪量化和腹部CT扫描，以检测是否有淋巴结病。我们还将进行分析，以探索甘油三酯、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇的相对贡献 ANGPTL4 LOF通过大规模人群研究调节CHD风险。在AIM-3中，我们将检测5,000例急性心肌梗死患者和5,000名对照的血浆ANGPTL8，这将启用(A)MI病例对照分析，(B)与ANGPTL8水平相关的基因发现分析，以及(C) 孟德尔随机化分析评估ANGPTL8水平与冠心病风险的因果关系。在22 ANGPTL8 LoF中携带者和22名非携带者，我们将测量OGTT和肝脏脂肪，以评估安全性和进行脂蛋白动力学研究探讨ANGPTL8 LOF与脂代谢的关系。