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: 7585808
• 负责人: DAVID Stuart SISCOVICK
• 金额: $ 72.18万
• 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/7585808
• 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）：申请的目的是检查脂肪酸（FA）代谢途径的常见遗传变异是否与人类突然心脏骤停（SCA）有关。脂肪酸代谢是复杂的，具有膜FAS和细胞内FA衍生物的多个决定因素，并且具有多种效应，即独立于细胞膜依赖性和膜，这可能会改变心脏离子通道和SCA风险。利用现有的血液标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代谢途径中常见变异与SCA风险的关联。我们将在相互关联的途径中检查92个候选基因，这些途径影响循环中的FA，心脏细胞对FAS的摄取，心脏能量和核信号传导以及类花生酸的产生。使用病例对照研究设计，我们将研究2600个欧美SCA病例和2600个欧美控制群体中候选基因和SCA风险的共同变异的关联；而且，我们将研究450例非裔美国人SCA案件和900名非裔美国人对照组的协会。 SCA病例的血液标本和临床数据将主要来自心脏骤停血液研究存储库（CABS-R），自1988年以来，自1988年以来就从SCA患者那里收集了血液样本，由医护人员在西雅图和金县（华盛顿）参加。控制标本和数据将来自对同一县进行的两项基于人群的心血管疾病研究。 Cabs-R中新的血液标本的收集以及心血管健康研究中的SCA病例，将使我们能够复制具有1000例新病例和1000个新控制的欧洲裔美国人的发现。除了检查主要影响外，我们还将使用2600个欧美SCA病例和仅病例设计的设计来研究基因基因相互作用和基因环境相互作用。我们还将检查心脏能量和类黄质途径的常见变化是否会改变红细胞膜N-3多不饱和FAS和具有SCA风险的反式脂肪酸的关联。我们对FA代谢相互关联途径的人类遗传变异的关注，这些途径有可能影响心脏离子通道功能和SCA风险。尽管用于解决目标的方法是良好的。拟议的研究源自SCA风险的遗传敏感性的信息将为基本，临床和人群的研究提供依据，并增强临床和公共卫生的努力，以降低社区中SCA的死亡率。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的专业知识与过去18年中的独特资源，DNA和临床数据相结合，从几个大种群中组装出来，以识别影响SCA敏感的新型遗传因素。 拟议的研究将提供有关FA代谢中人类遗传变异的关联和心脏骤停风险的新信息，这是美国心脏病引起的最常见死亡机制之一。人群中威胁生命的心律不齐的遗传敏感性因素的鉴定将提供对重要和毁灭性疾病的机制的见解，并可能确定了更好的预防目标。结果，拟议的研究对发展新知识的发展和知识的应用既有影响，以减少社区突然心脏骤停的死亡率。