Using genetic variation to study biology of blood lipids & coronary heart disease

利用遗传变异研究血脂生物学

• 批准号: 10458036
• 负责人: Pradeep Natarajan
• 金额: $ 74.86万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458036
• 关键词: Address; Adult; Age; Alleles; Atherosclerosis; Award; Biological; Biology; Cardiometabolic Disease; Cardiovascular Diagnostic Techniques; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cholesterol; Clinical; Clinical Trials; Collaborations; Computing Methodologies; Coronary heart disease; Coupled; Data; Development; Disease; Elderly; Ethics; Familial Hypercholesterolemia; Fatty Liver; Foundations; Genes; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Goals; Guidelines; Heart Diseases; Heritability; High Density Lipoprotein Cholesterol; Human Genetics; Individual; International; Intervention; Knowledge; LDL Cholesterol Lipoproteins; Leadership; Life; Lipids; Maps; Measures; Medicine; Mendelian randomization; Meta-Analysis; Methodology; Methods; Modality; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Online Systems; Pancreatitis; Pathway interactions; Phenotype; Plasma; Positioning Attribute; Prevention; Prevention strategy; Preventive care; Preventive therapy; Productivity; Publishing; Randomized Controlled Trials; Recording of previous events; Research; Risk; Risk Estimate; Risk Factors; Risk Reduction; Sampling; Scanning; Secure; Standardization; Statistical Methods; Therapeutic; Triglycerides; Variant; Veterans; Work; base; biobank; blood lipid; cardiometabolism; cardiovascular disorder risk; causal variant; clinical practice; cohort; data tools; epidemiology study; gene discovery; genetic analysis; genetic association; genetic variant; genome wide association study; genomic locus; heart disease risk; high risk; improved; innovation; insight; low and middle-income countries; middle age; multi-ethnic; multidisciplinary; new therapeutic target; novel; novel therapeutics; phenome; polygenic risk score; precision medicine; predictive marker; predictive modeling; prevent; public health relevance; risk mitigation; risk variant; sex; statistics; success; therapeutic development; therapeutic target; young adult

PROJECT SUMMARY / ABSTRACT Cardiovascular disease is the leading cause of death worldwide and elevated blood lipid levels are the strongest risk factor. The goal of this R01 proposal is to continue discovering and characterize genetic variants and genes associated with blood lipid levels using new methods, diverse cohorts, and clinical trials to identify new therapeutic targets and risk mitigation frameworks for lipids and cardiovascular disease. Our research team combines strengths in cardiovascular medicine, statistical genetics, high-throughput genetics and genomics, and development and application of innovative computational and statistical methods. In Aim 1, we will determine genetic variants associated with lipid levels leveraging over 2.5 million multi-ethnic samples. In Aim 2, we will perform phenome-wide scans for lipid-associated alleles and bi-directional multi-phenotype Mendelian randomization in ~1 million individuals. In Aim 3, we will build and evaluate multi-ethic polygenic risk scores for lipid levels in epidemiologic studies and completed clinical trials. In Aim 4 we will create a web- based compute engine to both provide our association results and calculate individual-level polygenic risk scores to facilitate the standardization of scores across studies. This proposal is a renewal of the previous Global Lipids Genetics Consortium (GLGC) award and established collaborative relationships, and will allow for the continued effort and coordination of the consortium. Completion of our aims will provide new insights that have the potential to catalyze breakthroughs in prevention, treatment, and diagnosis of cardiovascular disease and may serve as a model for other large-scale genetic studies.

项目概要/摘要 心血管疾病是全世界死亡的主要原因，血脂水平升高是导致死亡的主要原因 最强的风险因素。 R01 提案的目标是继续发现和表征遗传变异 使用新方法、不同队列和临床试验来识别与血脂水平相关的基因 血脂和心血管疾病的新治疗目标和风险缓解框架。我们的研究 团队结合了心血管医学、统计遗传学、高通量遗传学和 基因组学，以及创新计算和统计方法的开发和应用。在目标 1 中，我们 将利用超过 250 万个多种族样本来确定与血脂水平相关的遗传变异。在 目标 2，我们将对脂质相关等位基因和双向多表型进行全表组扫描 约 100 万人的孟德尔随机化。在目标 3 中，我们将建立并评估多伦理多基因风险 流行病学研究和已完成的临床试验中的血脂水平评分。在目标 4 中，我们将创建一个网络- 基于计算引擎来提供我们的关联结果并计算个体水平的多基因风险 分数，以促进跨研究分数的标准化。该提案是对之前提案的更新 全球脂质遗传学联盟 (GLGC) 授予并建立了合作关系，并将允许 感谢联盟的持续努力和协调。完成我们的目标将提供新的见解 有潜力促进心血管疾病预防、治疗和诊断方面的突破 疾病，并可作为其他大规模遗传研究的模型。