Pharmacogenomic effects of scavenger B1 in cardiovascular disease prevention

清除剂 B1 在心血管疾病预防中的药物基因组学效应

• 批准号: 10347622
• 负责人: Kathryn Tayo Hall
• 金额: $ 8.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10347622
• 关键词: Aspirin; Atherosclerosis; Beta Carotene; Candidate Disease Gene; Cardiometabolic Disease; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular Physiology; Catecholamines; Cause of Death; Cholesterol; Chronic Disease; Clinical Trials; Complement; Complex; Data; Data Set; Development; Disease; Drug Interactions; Elderly; Enzymes; Estrogens; Event; Failure; GUCY1A3 gene; Genes; Genetic; Genetic Heterogeneity; Goals; Grant; HDL receptor; Health; Hemorrhage; Heterogeneity; High Density Lipoprotein Cholesterol; Hormone replacement therapy; Individual; Lipids; Lipoproteins; Liver; Machine Learning; Malignant Neoplasms; Mediating; Metabolism; Modification; Myocardial Infarction; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Non-Prescription Drugs; Other Genetics; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Physicians; Placebos; Platelet aggregation; Population; Prevention; Prevention strategy; Prevention trial; Preventive; Preventive therapy; Process; Randomized; Randomized Clinical Trials; Reporting; Risk; Risk Factors; Safety; Signal Transduction; Soluble Guanylate Cyclase; Statistical Models; Stroke; System; Tissues; Translating; Translations; Validation; Vitamin E; Vitamins; Women' s Health; alpha Tocopherol; base; biobank; cancer prevention; cardiovascular disorder prevention; clinical practice; cohort; combinatorial; diabetes prevention program; genome wide association study; genomic locus; genomic variation; individualized prevention; machine learning method; macrophage; multi-ethnic; novel; prevent; random forest; randomized trial; receptor; response; uptake

PROJECT SUMMARY/ ABSTRACT Despite mixed evidence of efficacy, drugs like aspirin, and vitamin supplements, are widely used in the US population to prevent chronic diseases. The failure of randomized trials of these over-the-counter (OTC) drugs to consistently demonstrate efficacy, may in part be attributed to a complex interacting heterogeneity of genetic and other effects. Identifying pharmacogenomically defined subpopulations for benefit or harm from drugs and supplements, could enhance precision prevention of cardiovascular disease (CVD), one of the leading causes of death worldwide. Thus, pharmacogenomics, the study of how genomic variation modifies effects of pharmacologically active compounds, has the potential to guide development of precision CVD prevention strategies. Our group has identified candidate genes from multiple pathways related to cardiovascular function that modify the effects of aspirin, and vitamin E in randomized CVD prevention trials. Preliminary data from the Women’ Health Study (WHS), suggests that SCARB1, the gene encoding scavenger B1, a major HDL receptor, is a novel candidate gene for both aspirin and vitamin E effect modification in CVD prevention. Translation of pharmacogenomic markers requires identification of the full set of actionable pharmacogenomic targets, elucidation of their underlying mechanism, and replication of their effects in other cohorts. In this proposal, we examine SCARB1 pharmacogenomic effects on CVD in the WHS and four validation cohorts, ASPirin in Reducing Events in the Elderly (ASPREE), The Physician’s Health Study (PHS), The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), and The Partner’s Biobank (PBB), allowing broad generalizability of these findings. Given the complexity of CVD and the number of pathways highlighted by pharmacogenomic candidate genes, – estrogen and catecholamine metabolism (COMT), nitric oxide signaling (GUCY1A3), and cholesterol transport (LPA and SCARB1), – there are likely many more pharmacogenomic loci that give rise to a heterogeneity of effects. Identification of the full complement of treatment modifying genes is required to define effects of these overlapping pathways on efficacy and safety of CVD preventive therapy. Currently, discovery of pharmacogenomic loci is limited to candidate gene analysis because genome-wide association study (GWAS) datasets from clinical trials lack sufficient disease events to power classical statistical models. Machine learning approaches, like random forests (RF) obviate the need for statistical power offering an alternative path to discovery. Here, we propose to identify and validate combinatorial pharmacogenomic effects that influence aspirin and vitamin E in CVD prevention in The WHS and PBB by using the RF machine learning methodology. Thus, this proposal seeks to accelerate translation of precision cardiovascular disease prevention by identifying and validating individual and combinatorial effects of novel pharmacogenomic loci that influence the disease preventative effects of the widely used over-the-counter drugs, aspirin, and vitamin E.

项目摘要/摘要 尽管有效率的证据不同，但阿司匹林和维生素补充剂等药物被广泛用于 美国人口预防慢性疾病。这些非处方（OTC）随机试验的失败 药物始终证明效率，可能部分归因于复杂的相互作用异质性 遗传和其他影响。确定药物定义的子群，以获取福利或危害 药物和补充剂可以增强心血管疾病（CVD）的精确预防，其中之一 全球死亡的主要原因。那就是药物基因组学，研究基因组变异修饰剂的研究 药物活性化合物的作用，具有指导精度CVD的开发的潜力 预防策略。我们的小组已经从与 在随机CVD预防试验中改变阿司匹林和维生素E的影响的心血管功能。 妇女健康研究（WHS）的初步数据表明，编码清道夫的基因Scarb1 B1是一个主要的HDL接收器，是阿司匹林和维生素E效应修饰的新型候选基因 预防。药物基因组标记物的翻译需要识别完整的可操作集 药物基因组靶标，阐明其潜在机制以及在其他方面的复制 同伙。在此提案中，我们检查了WHS中CVD的Scarb1药物基因组基因组作用 验证队列，阿司匹林，减少老年人（ASPREE）的事件，医师的健康研究（PHS）， α-生育酚，β-胡萝卜素预防研究（ATBC）和伴侣的生物银行（PBB）， 允许这些发现的广泛概括。 鉴于CVD的复杂性以及药物基因组候选者突出显示的途径数量 基因 - 雌激素和儿茶酚胺代谢（COMT），一氧化氮信号（GUCY1A3）和胆固醇 运输（LPA和SCARB1）， - 可能会有更多的药物基因座产生 效应的异质性。确定完整完成治疗基因的完整完成需要定义 这些重叠途径对CVD预防疗法的有效性和安全性的影响。目前，发现 药物基因元基因座的限于候选基因分析，因为全基因组关联研究 （GWAS）来自临床试验的数据集缺乏足够的疾病事件，无法为经典的统计模型提供动力。 机器学习方法，例如随机森林（RF），消除了统计动力的需求 替代发现途径。在这里，我们建议识别和验证组合药物基因组效应 通过使用RF机器学习，在WHS和PBB的CVD预防中影响阿司匹林和维生素E 方法论。这是该提议试图加速精确心血管疾病的翻译 通过识别和验证新型药物基因座的个体和组合效应来预防 影响广泛使用的非处方药，阿司匹林和维生素E的疾病预防作用。