Genetic Determinants of Sudden Cardiac Death

描述（由申请人提供）：仅在美国，每年就有40万人死于心脏性猝死（SCD）。 超过一半的人在死亡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（包括SCN 5A、KVLQT 1、HERG、KCNE 1、KCNE 2和RyR 2）的突变与SCD高风险的单基因特征有关，例如长QT、Brugada、婴儿猝死综合征和儿茶酚胺多态性室性心动过速。 在不同的疾病状态下，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，这些基因中改变这些离子通道的功能或转录的序列变异可能在更广泛的人群中赋予室性心律失常和SCD的易感性。 该研究计划旨在确定上述候选基因中的序列变异是否与明显健康人群中SCD风险增加相关。 SCD病例将从NIH资助的五个前瞻性队列中收集，共有106，314例患者存在血液样本。 所有队列都非常好地描述了环境暴露，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例病例和对照中的所有编码序列变异和选定的非编码序列变异进行表征。 使用这些新的标记，我们将定义的单倍型块结构（连锁不平衡的SNPs）的六个基因。 然后，我们将采用巢式病例对照设计和条件logistic回归来测试编码区和非编码区的单倍型（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。 在资助期的前三年内，将确认约600例记录良好的SCD病例，这些病例将在年龄、性别、种族和地理位置方面与同一队列的两名对照受试者相匹配。 此外，基于已知的性别差异的表型表达的候选基因在原发性帕金森病，我们将专门检查性别差异的风险SCD相关的序列变异在这些基因。 研究结果将对我们理解SCD综合征和一般人群的危险分层产生重大影响。

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.