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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.

最近的几项研究表明，ANGPTL 3、4和8基因中的功能丧失（LoF）突变降低了ANGPTL 3、4和8基因的表达。富含甘油三酯的脂蛋白（TRL）和ANGPTL 3和ANGPTL 4 LoF变体的水平提供保护，冠心病（CHD）。因此，ANGPTL 3、4或8的抑制可以提供有吸引力的治疗方法，降低CHD风险的机制。然而，存在着许多悬而未决的不确定性，这三种蛋白质的完全或部分遗传缺陷对以下方面的影响：（i）TRL与 LDL与HDL介导CHD风险降低;（ii）对载脂蛋白B和载脂蛋白A含量范围的影响脂蛋白;（iii）这三种ANGPTL蛋白的相互关系;（iv）与 CHD风险;（v）完全或部分缺乏与葡萄糖耐量的相关性;（vi）安全性影响。该提案旨在通过利用ANGPTL 3、4和8的自然人类模型来解决这些差距已经在两个人群组中登记：（i）意大利队列（n = 613），其富集ANGPTL 3 人基因敲除（n = 22）;（ii）巴基斯坦基因组资源（PGR）（n ~ 100，000），富集了血缘关系。具体地，在AIM-1中，在22个三联体（22个ANGPTL 3无效纯合敲除和相等数目的ANGPTL 3缺失纯合敲除）中，杂合子和非携带者意大利，我们将测量：脂蛋白颗粒浓度，大小，组成、与进食和空腹状态下ANGPTL 8和ANGPTL 4水平的关系、代谢参数 (e.g.,口服葡萄糖耐量试验[OGTT]）和肝功能。我们还将评估ANGPTL 3的影响。缺乏对含载脂蛋白的载脂蛋白B动力学的影响，包括极低密度脂蛋白载脂蛋白B的产生率， VLDL转化为IDL和LDL apoB，以及VLDL、IDL和LDL apoB的清除率。我们还将评估疾病通过使用ANGPTL 3 LoF基因型和CHD风险与LDL-C、TRL和其他危险因素进行调解（n = 613）。在AIM-2中，将利用巴基斯坦生物资源PGR，并在22个ANGPTL 4 LoF载体和22个非携带者，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TRL-apoB和HDL apoA-I的动力学通过同位素示踪研究，进行OGTT、肝脏脂肪定量和腹部CT扫描，淋巴结病检查我们还将进行分析以探索TG、LDL-C和HDL-C的相对贡献通过大规模人群研究，ANGPTL 4 LoF介导CHD风险。在AIM-3中，我们将在5，000例新发MI病例和5，000例对照中测量血浆ANGPTL 8，使（a）MI病例对照分析，（B）与ANGPTL 8水平相关的基因发现分析，和（c）孟德尔随机化分析评估ANGPTL 8水平与CHD风险的因果关系。在22 ANGPTL 8 LoF中携带者和22名非携带者，我们将测量OGTT和肝脏脂肪，以评估安全性和行为脂蛋白动力学研究以检查ANGPTL 8 LoF与脂质代谢的关系。