Genetic Determinants of Sudden Cardiac Death

描述（由申请人提供）：仅在美国，心脏性猝死（SCD）每年就影响40万人。超过一半的人在死前没有心脏病的证据，我们识别那些有风险的人并因此预防SCD的能力很差。包括SCN5A、KVLQT1、HERG、KCNE1、KCNE2和RyR2在内的心脏离子通道基因突变与SCD高风险的单基因性状有关，如长qt间期综合征、Brugada、婴儿猝死综合征和儿茶酚胺能多态性室性心动过速。在多种疾病状态下，离子通道功能的改变可导致危及生命的室性心律失常。因此，这些基因的序列变异改变了这些离子通道的功能或转录，可能在更广泛的人群中导致室性心律失常和SCD的易感性。本研究计划旨在确定上述候选基因的序列变异是否与表面健康人群中SCD风险增加有关。SCD病例将从5个美国国立卫生研究院资助的前瞻性队列中收集，共有106,314人具有现有的血液样本。所有队列在环境暴露方面都有非常好的特征，并收集了心血管终点的医疗记录。我们将对来自这些队列的100例病例和对照的所有编码序列变异和选定的非编码序列变异进行表征。利用这些新的标记，我们将定义6个基因的单倍型块结构（连锁不平衡中的SNPs）。然后，我们将采用嵌套病例对照设计和条件逻辑回归来测试编码区和非编码区单倍型（单倍型标签snp）与SCD风险之间的关联。我们还将直接检测可能具有功能意义的单个基因座与SCD风险之间的关联。在资助期的前三年，估计有600例记录良好的SCD病例将得到确认，这些病例将在年龄、性别、种族和地理位置上与来自同一队列的两名对照受试者相匹配。此外，基于已知的原发性心律失常候选基因表型表达的性别差异，我们将专门研究与这些基因序列变异相关的SCD风险的性别差异。所产生的研究结果将对我们理解SCD综合征和普通人群的风险分层具有重大意义。

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) affects 400,000 individuals each year in the U.S. alone. Over half have no evidence of heart disease prior to death, and our ability to identify those at risk and therefore prevent SCD is poor. Mutations in cardiac ion channel genes including SCN5A, KVLQT1, HERG, KCNE1, KCNE2, and RyR2 have been implicated in monogenic traits with a high risk of SCD, such as the Iong-QT, Brugada, sudden infant death syndrome, and catecholaminergic polymorphic ventricular tachycardia. Alterations in ion channel function can result in life-threatening ventricular arrhythmias in diverse disease states. Therefore, sequence variants in these genes that alter function or transcription of these ion channels may confer a predisposition to ventricular arrhythmia and SCD in broader populations. This research program proposes to determine if sequence variants in the above candidate genes are associated with an increased risk of SCD in apparently healthy populations. Cases of SCD will be assembled from five NIH-funded prospective cohorts with a total of 106,314 individuals with existent blood samples. All cohorts are exceptionally wellcharacterized with respect to environmental exposures and have collected medical records on cardiovascular endpoints. We will characterize all coding sequence variation and selected non-coding sequence variation among 100 cases and controls from these cohorts. Using these novel markers, we will define the haplotype block structure (SNPs in linkage disequilibrium) for the six genes. We will then employ a nested case-control design and conditional logistic regression to test for associations between haplotypes (haplotype tag SNPs) in both coding and non-coding regions and SCD risk. We will also test directly for associations between single loci that may have functional significance and SCD risk. An estimated 600 cases of well-documented SCD will be confirmed over the first three years of the grant period, and these cases will be matched on age, sex, ethnicity, and geographic location to two control subjects from the same cohort. In addition, based upon known sex-differences in the phenotypic expression of the candidate genes in the primary arrhythmic disorders, we will specifically examine sex-differences in the risk of SCD associated with sequence variation in these genes. The findings generated will have substantial implications for our understanding of the SCD syndrome and risk stratification in the general population.