Genetic Determinants of Sudden Cardiac Death

描述(申请人提供)：仅在美国，每年就有40万人罹患心脏性猝死(SCD)。超过一半的人在死前没有心脏病的证据，我们识别风险人群并因此预防SCD的能力很差。心脏离子通道基因SCN5A、KVLQT1、HERG、KCNE1、KCNE2和RyR2的突变与SCD的高风险单基因性状有关，如长QT、Brugada、婴儿猝死综合征和儿茶酚胺能多形性室性心动过速。离子通道功能的改变可导致不同疾病状态下危及生命的室性心律失常。因此，这些基因中改变这些离子通道功能或转录的序列变异可能在更广泛的人群中容易发生室性心律失常和SCD。这项研究计划旨在确定上述候选基因中的序列变异是否与表面上健康的人群中SCD风险的增加有关。SCD病例将从NIH资助的五个预期队列中收集，总共有106,314名具有现有血液样本的个人。所有的队列在环境暴露方面都有非常好的特征，并收集了关于心血管终点的医疗记录。我们将从这些队列中鉴定100个病例和对照中的所有编码序列变异和选定的非编码序列变异。使用这些新的标记，我们将定义这六个基因的单倍型区块结构(连锁不平衡的SNPs)。然后，我们将采用嵌套病例对照设计和条件Logistic回归来检验编码区和非编码区的单倍型(单倍型标签SNPs)与SCD风险之间的关联。我们还将直接测试可能具有功能意义的单基因座与SCD风险之间的关联。在资助期的头三年，估计将有600例有充分记录的SCD病例得到确认，这些病例将在年龄、性别、种族和地理位置上与同一队列中的两名对照对象进行配对。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，我们将具体检查与这些基因序列变异相关的SCD风险的性别差异。所产生的发现将对我们理解SCD综合征和普通人群中的风险分层具有重大影响。

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.