HUMAN GENETIC VARIATION IN FATTY ACID METABOLISM AND SUDDEN CARDIAC ARREST

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心脏骤停（SCA）风险相关。脂肪酸代谢是复杂的，有多种膜FAs和细胞内FA衍生物的决定因素，以及多种可能改变心脏离子通道和SCA风险的膜依赖性和膜非依赖性效应。利用现有的血液标本和几个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风险的关系。我们将研究影响循环FAs、心脏细胞摄取FAs、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。采用病例对照研究设计，我们将在2600例欧美SCA病例和2600例欧美对照中检查候选基因的共同变异与SCA风险的关联；并且，我们将研究450名非裔美国人SCA病例和900名非裔美国人对照的关联。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储存库（CABS-R），该储存库自1988年以来收集了西雅图和金县（华盛顿）护理人员护理的SCA患者的血液样本。对照标本和数据将来自同一县开展的两项基于人群的心血管疾病研究。在CABS- R中收集新的血液标本，以及心血管健康研究中的SCA病例，将使我们能够在欧洲美国人中复制1000例新病例和1000例新对照的发现。除了检查主要影响外，我们还将使用2600例欧美SCA病例和仅病例设计来研究基因-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途径的共同变化是否会改变红细胞膜n-3多不饱和脂肪酸和反式脂肪酸与SCA风险的关联。我们对FA代谢相关途径的人类遗传变异的关注是新颖的，这些途径有可能影响心脏离子通道功能和SCA风险；尽管实现这些目标的方法是行之有效的。从拟议的研究中获得的SCA风险遗传易感性信息将为基础、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方面的专业知识与过去18年来从几个大型人群中收集的独特资源、DNA和临床数据相结合，以确定影响SCA易感性的新遗传因素。

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.