BACKGROUND:

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 the 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 long-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.

DESIGN NARRATIVE:

This study will determine if sequence variants in the cardiac ion channel genes are associated with an increased risk of sudden cardiac death in apparently healthy populations. Cases of sudden cardiac death will be assembled from five NIH-funded prospective cohorts with a total of 106,314 individuals with existent blood samples. All cohorts are exceptionally well characterized with respect to environmental exposures and have collected medical records on cardiovascular endpoints. The investigators will characterize all coding sequence variation and selected non-coding sequence variation among 100 cases and controls from these cohorts. Using these novel markers, they will define the haplotype block structure (SNPs in linkage disequilibrium) for the six cardiac ion channel genes, including SCN5A, KVLQT1, HERG, KCNE1, KCNE2, and RyR2. They 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 sudden cardiac death risk. They will also test directly for associations between single loci that may have functional significance and sudden cardiac death risk. An estimated 600 cases of well-documented sudden cardiac death 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, the investigators will specifically examine sex-differences in the risk of sudden cardiac death associated with sequence variation in these genes. The findings generated will have substantial implications for our understanding of the sudden cardiac death syndrome and risk stratification in the general population.