Abstract 4412: High Density tagSNP Candidate Gene Analysis Identifies IKs as a Major Modulator of Genetic Susceptibility to Drug Induced Long QT Syndrome
Introduction: Screening of coding and flanking regions of genes encoding cardiac ion channels has identified potential contributory DNA variants in <10 –20% of patients with drug-induced long QT syndrome (diLQTS). In this study, we tested the hypothesis that common variants tagging haplotype blocks in key genes controlling cardiac rhythm modify the risk of diLQTS, defined as documented torsades de pointes during treatment with a QT prolonging drug.
Methods: We studied 326 patients with diLQTS (documented torsades des pointes during treatment with a QT prolonging drug) from North America and Europe. Control populations included
probands that displayed <50 msec QT prolongation during initiation of QT-prolonging antiarrhythmics, n=476;
population controls from the KORA study, n=837.
All individuals were genotyped for 1536 SNPs using the Golden Gate platform. 1433 SNPs tagging common haplotype blocks (R2>0.8;minor allele frequency > 10%) were selected in 19 candidate genes: AKAP9 (20), ANK2 (118), CACNA1 (176), NOS1AP (130), CASQ2 (70), CAV3 (63), FKBP1B (13), GPDL1 (50), KCNE1 (71), KCNE2 (28), KCNH2 (67), KCNJ2 (42), KCNJ4 (9), KCNQ1 (151), RYR2 (240), SCN1B (24), SCN4B (54), SCN4A (25), SCN5A (82). Twenty non-synonymous SNPs previously implicated in arrhythmias were included.103 SNPs randomly distributed across the genome, were used to adjust for potential population stratification.
Results: Preliminary analysis identifies 4 SNPs) in KCNQ1, KCNE1, KCNE2, and SCN4B that distinguish diLQTS cases from drug-exposed and population controls (P<0.001 for both comparisons.
Conclusions: High density candidate tagSNP analysis implicates variability in Iks function as a major modulator of susceptibility to drug-induced long QT syndrome.
This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).