Abstract 1968: Common Variants in Cardiac Ion Channel Genes Are Associated With Sudden Cardiac Death
Background: Rare variants in cardiac ion channel genes are associated with sudden cardiac death in rare primary arrhythmic syndromes; however, it is unknown whether common variation in these same genes may contribute to SCD risk at the population level.
Methods and Results: We examined the association between 142 single nucleotide polymorphisms (SNPs) (137 tag and 5 nonsynonymous SNPs) in 5 cardiac ion channel genes, KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 and sudden and/or arrhythmic death in a combined nested case-control analysis among individuals of European ancestry enrolled in six prospective cohort studies. A total of 516 cases (188 women and 328 men) of sudden and/or arrhythmic cardiac deaths occurred among subjects with European ancestry in the six cohorts over an average follow-up of 13.0 years. Each case was matched to 3 controls, and conditional logistic regression with fixed effects meta-analysis was used to test for associations. After accounting for multiple testing, two SNPs (rs2283222 located in intron 11 in KCNQ1 and rs11720524 located in intron 1 in SCN5A) remained statistically significantly associated with sudden/arrhythmic death (FDR = 0.01 and 0.03 respectively). Each increasing copy of the major T allele of rs2283222 or the major C allele of rs1172052 was associated with a significantly increased odds of SCD (OR = 1.36, 95% CI 1.16 –1.60, P = 0.0002; and OR = 1.30, 95% CI 1.12–1.51, P = 0.0005, respectively). Control for cardiovascular risk factors and/or limiting the analysis to definite SCDs did not significantly alter these relationships. None of the five nonsynonymous SNPs tested were associated with SCD with or without risk factor adjustment.
Conclusion: Common intronic variants in KCNQ1 and SCN5A are associated with SCD in individuals of European ancestry. Further investigation into the functional abnormalities associated with non-coding variation in these genes may lead to important insights into predisposition to lethal arrhythmias.