Abstract 748: Common Genetic Variation In KCNJ11 Influences The Risk Of Arrhythmias In Patients With ICD And Structural Heart Disease
Introduction: Clinical risk stratification tests regarding sudden cardiac death (SCD) in patients(pts) with coronary artery disease (CAD) and dilated cardiomyopathy (DCM) have a limited predictive value. Thus it would be desirable to develop novel risk stratification strategies, which involve knowledge of molecular and genetic susceptibility to cardiac arrhythmias. Therefore, we aimed to determine whether variations in genes involved in the cardiac action potential modify the risk of cardiac arrhythmias and SCD in CAD and DCM.
Methods: The case population consisted of 225 pts who received an ICD after documented arrhythmic events (159 CAD and 66 DCM pts). Control population consisted of 408 (301 CAD and 107 DCM) pts without an ICD and evidence of life-threatening arrhythmias. In an exon-centered approach, 90 SNPs were selected in 3 genes involved in cardiac depolarization and repolarization (KCNQ1, KCNH2, SCN5A) and 2 genes coding for ATP-dependent potassium channels (ABCC9, KCNJ11). Genotyping was performed using MALDI-TOF MS genotyping platform. Statistical analyses included chi-square statistics for recessive and dominant inheritance models and Armitage’s test for trend for additive genotype effects.
Results: In the KCNJ11, an intronic SNP rs5222 was highly significantly associated with the ICD status (p= 0.005, odds ratio (OR) 2.26 [95% CI 1.23– 4.18], for recessive model of inheritance), creating a common risk haplotype with other markers, including rs5218. Furthermore, when analyzing the CAD population separately, two SNPs (intronic SNP rs2075870 in KCNQ1 and intronic SNP rs5222 in KCNJ11) were significantly associated with the ICD status (p=0.02 and p=0.01, respectively, for dominant and recessive model of inheritance). In the DCM population, the intronic marker rs876088 in the KCNH2 gene was highly significantly associated with the ICD status (p=0.001 for the trend test).
Conclusion: SNPs in genes coding for cardiac channel proteins modify the risk for arrhythmic events in pts with CAD and DCM. Importantly, a common risk haplotype including the SNP rs5222 in the KCNJ11 gene seems to influence the risk similarly in both groups (DCM and CAD) and thus may function as an arrhythmic risk harbinger in pts with structural heart disease.