HUMAN GENETIC VARIATION IN FATTY ACID METABOLISM AND SUDDEN CARDIAC ARREST

描述(由申请人提供)：申请的目标是检查脂肪酸(FA)代谢途径的常见遗传变异是否与人类心脏骤停(SCA)风险有关。脂肪酸代谢是复杂的，膜FAs和细胞内FA衍生物的多种决定因素，以及细胞膜依赖和膜非依赖的多种效应，可能改变心脏离子通道和SCA的风险。利用现有的血液样本和几个特征良好的基于人群的研究的临床数据，我们建议调查FA代谢途径的常见变异与SCA风险的关系。我们将研究92个候选基因，这些基因通过相互关联的途径影响循环脂肪酸、心肌细胞对脂肪酸的摄取、心脏能量和核信号，以及二十烷类化合物的产生。使用病例对照研究设计，我们将在2600例欧美SCA病例和2600例欧美对照中检验候选基因常见变异与SCA风险的关联；我们将在450例非裔美国SCA病例和900名非裔美国对照中检验这种关联。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储存库(CABS-R)，自1988年以来，该中心一直在西雅图和华盛顿州金县由护理人员护理的SCA患者身上采集血液样本。对照样本和数据将来自在同一县进行的两项以人群为基础的心血管疾病研究。在CABS-R中收集新的血液样本，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复制1000个新病例和1000个新对照的发现。除了检验主效应外，我们还将使用2600个欧美SCA病例和一个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二十烷类化合物途径的共同变异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风险的关系。我们对FA代谢相关途径中可能影响心脏离子通道功能和SCA风险的人类遗传变异的关注是新颖的；尽管用于解决这些目标的方法已经建立得很好。从拟议的研究中获得的关于SCA风险的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方面的专业知识与过去18年从几个大型人群收集的独特资源、DNA和临床数据相结合，以确定影响SCA易感性的新遗传因素。 这项拟议的研究将提供有关人类FA代谢的遗传变异与心脏骤停风险之间的关联的新信息，心脏骤停是美国最常见的心脏病死亡机制之一。在人类人群中识别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一种重要的破坏性疾病的机制，并可能确定更好的预防目标。因此，这项拟议的研究对开发新知识和应用知识降低社区心脏骤停死亡率具有重要意义。

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.