The Genetic and Molecular Basis of Cholesterol Efflux

胆固醇流出的遗传和分子基础

• 批准号: 10307083
• 负责人: Anand Kumar Rohatgi
• 金额: $ 69.66万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307083
• 关键词: ATP binding cassette transporter 1; Albumins; Amyloid; Antiatherogenic; Apolipoprotein A-I; Atherosclerosis; Biological Process; Blood Circulation; Cause of Death; Cholesterol; Code; Data; Deposition; Disease; Ethnic Origin; Event; Excision; Family; Future; Genetic; Genomics; Genotype; Goals; Heart; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Homeostasis; Human; Individual; Link; Lipids; Liquid Chromatography; Maps; Mass Spectrum Analysis; Measures; Mediator of activation protein; Mendelian randomization; Metabolic; Molecular; Multi-Ethnic Study of Atherosclerosis; Participant; Pathway interactions; Performance; Phenotype; Plasma; Population; Population Study; Process; Proteins; Proteomics; Reporting; Research; Risk Factors; Serum; Sphingolipids; Time; United States; Variant; Work; atheroprotective; cardiometabolism; cholesterol transporters; cohort; exome sequencing; genetic association; genetic variant; genome-wide; improved; improved outcome; inter-individual variation; link protein; liquid chromatography mass spectroscopy; macrophage; metabolic phenotype; metabolomics; multi-ethnic; novel; particle; population based; prevent; reverse cholesterol transport; risk prediction; sex; trait

Project Summary Low high-density lipoprotein cholesterol (HDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of death. However, strategies to improve atheroprotection by raising HDL-C levels have failed to improve outcomes. Macrophage- specific cholesterol efflux is the first critical step of reverse cholesterol transport, a key atheroprotective pathway. Cholesterol efflux is inversely associated with incident ASCVD events; however, the mechanisms that underlie variation in cholesterol efflux are unknown. There is a critical need to identify factors that regulate cholesterol efflux to advance understanding of the reverse cholesterol transport pathway, a biological process that has broad implications across a variety of disease states including atherosclerosis. The overall objective of this proposal is to systematically ascertain the genetic and molecular factors governing variation in cholesterol efflux. We propose to carry out our objective by using two large, population- based multi-ethnic cohorts, the Dallas Heart Study (DHS) and the Multi-Ethnic Study of Atherosclerosis (MESA) to pursue the following aims: 1) determine the contribution of genetic factors to inter-individual variability in cholesterol efflux and whether these factors are causally associated with ASCVD; and 2) identify the metabolite and protein signature of cholesterol efflux in a sex- and ethnicity-specific manner. We expect to characterize the genetic, metabolic, and protein regulators of cholesterol efflux to support future studies targeting manipulation of the reverse cholesterol transport pathway.

项目摘要 低高密度脂蛋白胆固醇（HDL-C）是动脉粥样硬化的主要危险因素 心血管疾病（ASCVD）是导致死亡的主要原因。然而，改善战略 通过提高HDL-C水平来预防动脉粥样硬化并不能改善预后。巨噬细胞- 特异性胆固醇流出是胆固醇逆向转运的第一个关键步骤， 动脉粥样硬化保护途径胆固醇流出与ASCVD事件呈负相关 事件;然而，胆固醇流出变化的机制尚不清楚。 有一个关键的需要，以确定因素，调节胆固醇流出，以促进 了解胆固醇逆向转运途径，这是一个具有广泛生物学意义的过程。 包括动脉粥样硬化在内的多种疾病状态的影响。的总体目标 这一建议是系统地确定控制变异的遗传和分子因素 胆固醇流出量我们建议利用两个人口众多的- 基于多种族的队列，达拉斯心脏研究（DHS）和多种族研究， 运动疗法（梅萨）追求以下目标：1）确定遗传的贡献， 胆固醇流出的个体间变异性的因素，以及这些因素是否是因果关系 与ASCVD相关; 2）确定胆固醇流出的代谢产物和蛋白质特征 以性别和种族的方式。我们希望能描述遗传、代谢和 胆固醇流出的蛋白质调节剂，以支持未来的研究， 逆转胆固醇转运途径。

项目成果

Is there a connection between HDL and atrial fibrillation?

• DOI: 10.1016/j.jacl.2022.06.010
• 发表时间: 2022-07
• 期刊: Journal of clinical lipidology
• 影响因子: 4.4
• 作者: R. Mackey;Anand Rohatgi

HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research.

• DOI: 10.1161/circulationaha.120.044221
• 发表时间: 2021-06-08
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Rohatgi A;Westerterp M;von Eckardstein A;Remaley A;Rye KA
• 通讯作者: Rye KA

Proteomic Determinants of Variation in Cholesterol Efflux: Observations from the Dallas Heart Study.

• DOI: 10.3390/ijms242115526
• 发表时间: 2023-10-24
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Higher High-Density Lipoprotein Cholesterol-Good Omen, Bad Omen, or Not an Omen at All.

高密度脂蛋白胆固醇升高——好兆头、坏兆头或根本不是兆头。

• DOI: 10.1001/jamacardio.2022.5143
• 发表时间: 2023
• 期刊: JAMA cardiology
• 影响因子: 24
• 作者: Wilkins,John;Rohatgi,Anand
• 通讯作者: Rohatgi,Anand

Novel Size-Based High-Density Lipoprotein Subspecies and Incident Vascular Events.

• DOI: 10.1161/jaha.123.031160
• 发表时间: 2023-11-07
• 期刊: JOURNAL OF THE AMERICAN HEART ASSOCIATION
• 影响因子: 5.4
• 作者: Deets, Austin;Joshi, Parag H.;Chandra, Alvin;Singh, Kavisha;Khera, Amit;Virani, Salim S.;Ballantyne, Christie M.;Otvos, James D.;Dullaart, Robin P. F.;Gruppen, Eke G.;Connelly, Margery A.;Ayers, Colby;Navar, Ann Marie;Pandey, Ambarish;Wilkins, John T.;Rohatgi, Anand
• 通讯作者: Rohatgi, Anand