Abstract 1893: Common Genetic Variation in Ion Channel Genes Associated With Sudden Cardiac Arrest Risk
Background: Mutations in ion channel genes have been associated with inherited arrhythmic disorders such as Long QT, Short QT, and Brugada Syndromes, and Catecholaminergic Polymorphic Ventricular Tachycardia. We investigated whether common genetic variations in these genes are associated with sudden cardiac arrest (SCA) risk.
Methods: In a population-based case-control study set in King County WA, we genotyped 2015 SCA cases (mean age 67, 76% male) and 2337 age- and gender-matched controls of European descent for 223 single nucleotide polymorphisms (SNPs) in eight genes (KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, RYR2). We examined association of SNPs with SCA risk using logistic regression, adjusted for age and gender, and used permutation testing to account for within gene multiple comparisons.
Results: Common variation in four (SCN5A, ANK2, KCNJ2, and RYR2) of eight genes examined were associated with SCA risk. In SCN5A (permutation p=0.013), rs6599223 (minor allele frequency (MAF)=17%) was associated with higher SCA risk (OR=1.24, 95%CI=1.10 –1.39), and rs6768135 (MAF=23%) was associated with lower risk (OR=0.86, 95%CI=0.78 – 0.95). In KCNJ2 (permutation p=0.028), rs173135 (MAF=12%) was associated with higher SCA risk (OR=1.19, 95%CI=1.04 –1.37). In ANK2 (permutation p=0.067), rs29324 (MAF=29%) was associated with lower SCA risk (OR=0.86, 95%CI=0.78 – 0.94). In RYR2 (permutation p=0.067), SNP rs790900 (MAF=33%) was associated with lower risk (OR=0.86, 95%CI=0.78 – 0.94). Creating a risk score from these top five SNPs, each additional disadvantageous allele conferred a 17% increase in SCA risk (OR=1.17, 95%CI=1.12–1.22). Compared to those in the lowest quintile of risk, those in the top quintile had a 78% increase in risk of SCA (OR=1.78, 95%CI=1.39 –2.28).
Conclusions: Variation in SCN5A, KCNJ2, ANK2, and RYR2 are associated with SCA risk in a large population-based case-control study. Our findings, if replicated, suggest that common variation in ion channel genes influence SCA risk in the general population.