HUMAN GENETIC VARIATION IN FATTY ACID METABOLISM AND SUDDEN CARDIAC ARREST

脂肪酸代谢和心脏骤停的人类遗传变异

• 批准号: 7753653
• 负责人: DAVID Stuart SISCOVICK
• 金额: $ 71.76万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-07 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753653
• 关键词: Accounting; Acyl Coenzyme A; Acylation; Address; Affect; African American; Alleles; American; Attention; Blood; Blood specimen; Candidate Disease Gene; Cardiac; Cardiology; Cardiovascular Diseases; Cardiovascular system; Case-Control Studies; Cell membrane; Cells; Cessation of life; Clinical; Clinical Data; Coenzyme A; Cohort Studies; Collection; Communities; Complex; Coronary heart disease; County; DNA; Data; Development; Dietary intake; Disease; Eicosanoid Production; Eicosanoids; Environmental Risk Factor; Erythrocytes; Essential Fatty Acids; Etiology; European; Fatty Acids; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Goals; Health; Heart Arrest; Heart Diseases; Hospitals; Human; Human Genetics; Individual; Ion Channel; Ions; Knowledge; Label; Life; Mediating; Medicine; Membrane; Metabolic Pathway; Methods; Modeling; Molecular Genetics; Nuclear; Nuclear Receptors; Paramedical Personnel; Pathway interactions; Patients; Pattern; Polyunsaturated Fatty Acids; Population; Population Study; Positioning Attribute; Predisposition; Prevention; Production; Public Health; Receptor Signaling; Research; Research Design; Research Methodology; Resources; Risk; Signal Pathway; Signal Transduction; Specimen; Stratification; Trans Fatty Acids; United States; Variant; Ventricular Arrhythmia; Ventricular Fibrillation; Washington; Work; design; family influence; fatty acid metabolism; fatty acid oxidation; gene environment interaction; gene interaction; genetic epidemiology; heart electrical activity; high risk; insight; mortality; novel; population based; receptor; repository; uptake

DESCRIPTION (provided by applicant): The goal of the application is to examine whether common genetic variation in fatty acid (FA) metabolic pathways is associated with sudden cardiac arrest (SCA) risk in humans. Fatty acid metabolism is complex with multiple determinants of membrane FAs and intracellular FA derivatives, and multiple effects, cell membrane-dependent and membrane independent, that might alter cardiac ion channels and SCA risk. Taking advantage of existing blood specimens and clinical data from several well characterized population- based studies, we propose to investigate the association of common variation in FA metabolic pathways with the risk of SCA. We will examine 92 candidate genes in interrelated pathways that influence circulating FAs, the uptake of FAs by cardiac cells, cardiac energetics and nuclear signaling, and eicosanoid production. Using a case-control study design, we will examine the association of common variation in candidate genes and SCA risk in 2600 European-American SCA cases and 2600 European-American controls; and, we will examine the associations in 450 African-American SCA cases and 900 African-American controls. Blood specimens and clinical data for the SCA cases will come primarily from the Cardiac Arrest Blood Study Repository (CABS-R), where blood samples have been collected since 1988 from patients with SCA attended by paramedics in Seattle and King County (Washington). Control specimens and data will be from two population-based studies of cardiovascular disease conducted in the same county. The collection of new blood specimens in the CABS- R, together with SCA cases from the Cardiovascular Health Study, will allow us to replicate the findings among European Americans with 1000 new cases and 1000 new controls. In addition to examining main effects, we will use the 2600 European-American SCA cases and a case-only design to investigate gene-gene interactions and gene-environment interactions. We also will examine whether common variation in cardiac energetics and eicosanoid pathways modifies the associations of red cell membrane n-3 polyunsaturated FAs and trans-fatty acids with SCA risk. Our focus on human genetic variation in interrelated pathways of FA metabolism that have the potential to influence cardiac ion channel function and SCA risk is novel; although the methods used to address the aims are well-established. The information on genetic susceptibility to SCA risk derived from the proposed research will inform basic, clinical, and population-based research and enhance clinical and public health efforts to reduce mortality from SCA in the community. In short, we combine expertise in cardiovascular and genetic epidemiology, statistical genetics, molecular cardiology, genomics, and fatty acid metabolism with unique resources, DNA and clinical data assembled over the past 18 years from several large populations, to identify novel genetic factors that influence susceptibility to SCA. The proposed study will provide novel information on the association of human genetic variation in FA metabolism and the risk of sudden cardiac arrest, one of the most common mechanisms of mortality due to heart disease in the United States. The identification of genetic susceptibility factors to life-threatening ventricular arrhythmia in human populations will provide insight into the mechanisms of an important and devastating disease, and perhaps identify better targets for prevention. As a result, the proposed research has implications both for the development of new knowledge and the application of knowledge to reduce mortality from sudden cardiac arrest in the community.

描述（由申请人提供）：该申请的目的是检查脂肪酸（FA）代谢途径中常见的遗传变异是否与人类心脏骤停（SCA）风险相关。脂肪酸代谢很复杂，涉及膜 FA 和细胞内 FA 衍生物的多个决定因素，以及细胞膜依赖性和膜非依赖性的多种效应，可能会改变心脏离子通道和 SCA 风险。利用现有的血液样本和来自几项基于人群的研究的临床数据，我们建议研究 FA 代谢途径的常见变异与 SCA 风险之间的关联。我们将检查影响循环 FA、心肌细胞对 FA 的摄取、心脏能量学和核信号传导以及类二十烷酸产生的相关途径中的 92 个候选基因。我们将采用病例对照研究设计，在 2600 例欧美 SCA 病例和 2600 例欧美对照中检查候选基因的常见变异与 SCA 风险之间的关联；我们将研究 450 个非裔美国人 SCA 病例和 900 个非裔美国人对照病例中的关联。 SCA 病例的血液样本和临床数据将主要来自心脏骤停血液研究存储库 (CABS-R)，该库自 1988 年以来一直从西雅图和金县（华盛顿）护理人员护理的 SCA 患者身上采集血液样本。对照标本和数据将来自在同一县进行的两项基于人群的心血管疾病研究。 CABS-R 中收集的新血液样本以及心血管健康研究中的 SCA 病例将使我们能够在欧洲裔美国人中通过 1000 个新病例和 1000 个新对照来复制研究结果。除了检验主效应之外，我们还将使用 2600 个欧美 SCA 案例和纯案例设计来研究基因-基因相互作用和基因-环境相互作用。我们还将研究心脏能量学和类二十烷酸途径的常见变化是否会改变红细胞膜 n-3 多不饱和 FA 和反式脂肪酸与 SCA 风险的关联。我们对 FA 代谢相关途径中人类遗传变异的关注是新颖的，这些变异有可能影响心脏离子通道功能和 SCA 风险。尽管用于实现这些目标的方法是既定的。从拟议研究中获得的关于 SCA 风险遗传易感性的信息将为基础、临床和基于人群的研究提供信息，并加强临床和公共卫生工作，以降低社区 SCA 死亡率。简而言之，我们将心血管和遗传流行病学、统计遗传学、分子心脏病学、基因组学和脂肪酸代谢方面的专业知识与过去 18 年从多个大人群中收集的独特资源、DNA 和临床数据相结合，以确定影响的新遗传因素对 SCA 的易感性。 拟议的研究将提供有关人类 FA 代谢遗传变异与心脏骤停风险之间关系的新信息，心脏骤停是美国心脏病最常见的死亡机制之一。识别人群中危及生命的室性心律失常的遗传易感因素将有助于深入了解这种重要且毁灭性疾病的机制，并可能确定更好的预防目标。因此，拟议的研究对于新知识的开发和知识的应用以降低社区心脏骤停的死亡率都有影响。