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Characterization of a Lysosomal Acid Lipase Variant Associated with Coronary Disease

与冠心病相关的溶酶体酸性脂肪酶变体的表征

基本信息

批准号：
9121663
负责人：
Trent Evans
金额：
$ 4.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9121663
关键词：
Acid Lipase Adverse effects Affect Biological Assay Blood CRISPR/Cas technology Cardiovascular Diseases Cause of Death Cells Cholesterol Cholesterol Esters Cholesterol Homeostasis Code Coronary Arteriosclerosis Coronary heart disease DNA Development Enzymes Evaluation Foam Cells Functional disorder Genetic Polymorphism Genetic Risk Goals Homeostasis Human Genetics Hydrolysis In Vitro Link Lipase Lipids Lysosomes Magnetism Mediating Messenger RNA Metabolism Modeling Molecular Mus Nonesterified Fatty Acids Pathogenesis Patients Peptide Signal Sequences Phenotype Population Process Proteins Publishing Recording of previous events Research Research Personnel Research Training Risk Role Sampling Serum Testing Transcript Triglycerides Untranslated RNA Variant Western Blotting cohort disorder risk enzyme activity experience genome wide association study glycosylation human disease hypercholesterolemia induced pluripotent stem cell insight lipid metabolism loss of function mutation macrophage metabolic phenotype monocyte novel prevent protein expression public health relevance research study response risk variant trafficking translational approach uptake

项目摘要

DESCRIPTION (provided by applicant): Two tightly linked common intronic variants of the Lysosomal Acid Lipase (LIPA) locus, present in nearly one- third of the population, have been shown to increase the risk of coronary artery disease (CAD) by 13-17% in large-scale genome-wide association studies. LIPA mediates the hydrolysis of cholesteryl esters and patients with rare loss-of-function mutations develop hypercholesterolemia and CAD. However, these common LIPA variants are intronic, not associated with lipid abnormalities, and result in increased LIPA transcripts in monocytes, a constellation of findings that has prevented further mechanistic understanding. We have discovered a previously unrecognized coding variant in close linkage with the intronic variants that is equally associated with CAD risk. We hypothesize that the coding variant, with potential consequences to LIPA enzyme activity and cellular cholesterol homeostasis, is the culprit link with cardiovascular disease. This concept will be evaluated by assessing the effect of the coding variant on levels of LIPA mRNA, protein, and enzyme activity in circulating monocytes isolated from cohorts of patients with and without known CAD. In order to definitely implicate the coding variant, induced pluripotent stem cell derived monocytes/macrophages harboring the coding variant in the absence of the confounding intronic variants will be studied. This model will allow determination of whether the coding variant in isolation alters LIPA mRNA, protein, and enzyme activity. Further mechanistic characterization will include effects on crucial lipid metabolic phenotypes implicated in CAD pathogenesis including cholesterol efflux, lipid uptake, and foam cell formation. Finally, given that the coding variant lies in the signal peptide region of LIPA, its impact on LIPA trafficking, maturation, and secretion will be assessed as potential mechanisms for dysfunction. Taken together, this highly translational set of experiments will provide the first mechanistic insight ito an important genetic risk allele associated with CAD.