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.

最近的几项研究表明，ANGPTL3、4 和 8 基因的功能丧失 (LoF) 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，存在许多突出的不确定性，与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 TRL 的相对贡献低密度脂蛋白 (LDL) 与高密度脂蛋白 (HDL) 在降低冠心病风险方面的作用； (ii) 对apoB和apoA含有范围的影响脂蛋白； (iii) 这三种 ANGPTL 蛋白的相互关系； (iv) 剂量-反应关系冠心病风险； (v) 完全或部分缺乏与葡萄糖耐量的相关性； (vi) 安全影响。该提案旨在通过利用 ANGPTL3、4 和 8 的自然人体模型来解决这些差距缺陷，已纳入两个人群：(i) 富含 ANGPTL3 的意大利队列 (n = 613) 人类基因敲除（n = 22）； (ii) 巴基斯坦基因组资源 (PGR)（n ~ 100,000）因血缘关系而丰富。具体来说，在 AIM-1 中，在 22 个三重奏中（22 个 ANGPTL3 无效纯合敲除和相同数量的来自意大利的杂合子和非携带者），我们将测量：脂蛋白颗粒浓度、大小和组成、进食和空腹状态下 ANGPTL8 和 ANGPTL4 水平的关系、代谢参数（例如，口服葡萄糖耐量试验 [OGTT]）和肝功能。我们还将评估 ANGPTL3 的影响含apoB脂蛋白的动力学缺陷，包括VLDL apoB生成率、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 ANGPTL3 LoF 基因型和 LDL-C、TRL 和其他危险因素来调节 CHD 风险 (n = 613)。在 AIM-2 中，将利用巴基斯坦生物资源、PGR 以及 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 的动力学通过基于同位素示踪的研究并进行 OGTT、肝脂肪定量和腹部 CT 扫描检查淋巴结肿大。我们还将进行分析，探讨 TG、LDL-C 和 HDL-C 的相对贡献通过基于大规模人群的研究，调节 ANGPTL4 LoF 赋予的 CHD 风险。在 AIM-3 中，我们将测量 5,000 例 MI 病例和 5,000 例对照者的血浆 ANGPTL8，这将实现 (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) 孟德尔随机分析评估 ANGPTL8 水平与 CHD 风险的因果关系。 22 ANGPTL8 LoF 携带者和 22 名非携带者，我们将测量 OGTT 和肝脂肪以评估安全状况和行为脂蛋白动力学研究以检查 ANGPTL8 LoF 与脂质代谢的关系。