Abstract 11615: Common and Rare Gene Variants in Sudden Cardiac Death: The FinSCDgen Study
Background: Over half of cardiac deaths occur suddenly out of hospital. Family history of sudden cardiac death (SCD) is a risk factor for SCD but the underlying genetic components are largely unknown.
Objectives: We investigated common and rare variants, previously associated with arrhythmia or electrocardiographic variables, as potential risk factors for SCD. We also examined changes in gene expression levels associated with the observed SCD risk alleles.
Methods: We studied 28 common and 10 rare gene variants in a meta-analysis of 4 population cohorts (FINRISK 1992, 1997, 2002, Health 2000, n = 27,629) and 2 forensic autopsy series (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 694) using proportional hazards and logistic regression. A total of 716 probable and possible SCD cases were identified using registry-based health and autopsy data. RNA was extracted from peripheral blood samples of 510 unrelated individuals and expression analysis was performed using linear regression.
Results: Two common variants were associated with SCD: SCN5A rs41312391 (relative risk [RR] 1.27 per minor T allele, 95% CI 1.11-1.45, P = 3.4x10-4) and rs2200733 in 4q25 (RR 1.28 per minor T allele, 95% CI 1.11-1.48, P = 7.9x10-4). In addition, association with 9p21 (rs2383207, RR 1.13 per G allele, 95% CI 1.01-1.26, P = 0.036) was replicated. The rs2200733 minor allele was associated with increased expression of PITX2 (P = 0.013) and the rs41312391 minor allele with increased expression of WDR48 (P = 0.037). Of the 716 SCD cases, 7 (1.0%) carried 1 of the 10 rare mutations: 2 carried PKP2 Q59L, 1 KCNH2 L552S, 3 KCNH2 R176W, and 1 RYR2 R3570W.
Conclusions: Two novel common variants are associated with SCD: rs2200733 in 4q25, previously associated with atrial fibrillation, and rs41312391 in an intron of SCN5A. The association of 4q25 with arrhythmia and SCD may involve expression changes of PITX2, which encodes a transcription factor contributing to cardiac morphogenesis. Rare mutations predisposing to ventricular arrhythmias, such as arrhythmogenic right ventricular cardiomyopathy or long QT syndrome, may be detected in occasional individuals with SCD not previously known to be at risk.
- © 2011 by American Heart Association, Inc.