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：
10186801
负责人：
Daniel James Rader
金额：
$ 70.02万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186801
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较低的功能丧失（LOF）突变降低富含甘油三酸酯的水平富脂蛋白（TRL）和Angptl3和Angptl4 Lof变体可保护冠心病（CHD）。因此，抑制Angptl3，4或8可以提供有吸引力的治疗方法降低CHD风险的机制。但是，存在许多出色的不确定性，与这三种蛋白质的完全或部分遗传缺乏对：（i）TRL VS的相对贡献 LDL vs HDL介导了冠心病风险降低；（ii）对包含APOB和APOA范围的影响脂蛋白；（iii）这三种Angptl蛋白的相互关系；（iv）与冠心病风险；（v）完全或部分缺陷与葡萄糖耐量的相关性；（vi）安全的影响。该建议旨在通过利用Angptl3、4和8的自然人类模型来解决这些差距缺乏症，已经参与了两个人口组：（i）意大利队列（n = 613）富含angptl3 人类淘汰（n = 22）; （ii）巴基斯坦基因组资源（PGR）（n〜100,000）富含血缘关系。具体而言，在AIM-1中，在22个三重奏中来自意大利的杂合子和非载体），我们将测量：脂蛋白颗粒浓度，大小和在FED和禁食状态下的组成，与ANGPTL8和ANGPTL4水平的关系，代谢参数（例如，口服葡萄糖耐量测试[OGTT]）和肝功能。我们还将评估Angptl3的影响含有脂蛋白的APOB动力学的缺乏，包括VLDL APOB生产率，转化率 VLDL至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LDL-C，TRL和其他危险因素使用Angptl3 LoF基因型和CHD风险进行调解（n = 613）。在AIM-2中，将利用巴基斯坦Bioresource，PGR和22个Angptl4 Lof载体和22个非 - 载体，我们将测量：脂蛋白颗粒浓度，大小和成分，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HDL APOA-I的动力学通过同位素追踪的研究并进行OGTT，肝脂肪定量和腹部CT扫描至测试淋巴结肿大。我们还将进行分析以探索TG，LDL-C和HDL-C的相对贡献在介导ANGPTL4 LOF通过大型基于人群的研究中赋予的CHD风险中。在AIM-3中，我们将在5,000例MI病例和5,000个控件中测量血浆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） Mendelian随机分析以评估具有CHD风险的ANGPTL8水平的因果关系。在22个angptl8 lof中运营商和22个非携带者，我们将测量OGTT和肝脂肪，以评估安全性和行为脂蛋白动力学研究以检查ANGPTL8 LOF与脂质代谢的关系。