Abstract 1971: Genome-wide Association Study Identifies Novel Genomic Regions Associated With Drug-induced Long Qt Syndrome
Introduction A serious side-effect of antiarrhythmic and many other agents is drug-induced long QT syndrome (diLQTS) with torsades de pointes. To test the role of common genetic variation in diLQTS risk requires large numbers of cases and controls.
Methods Seven centers in a Leducq Network collaborated to collect cases of diLQTS and controls for a genome-wide association study (GWAS). Controls were subjects exposed to QT-prolonging antiarrhythmics with ΔQTc<50 and no QTc>500. Samples from this collaboration were genotyped using the Illumina Infinium 610Quad BeadChip at the RIKEN center in Japan.
Results Nine DNA samples were of insufficient quality and were omitted from subsequent analyses. Of the 592,532 SNPs targeted for genotyping, 28,137 SNPs were omitted for low genotyping efficiency or call rates (≤90%), 3,484 SNPs were omitted for being monomorphic in the dataset, and 38,242 SNPs were omitted for having a minor allele frequency ≤1%. Hardy Weinberg Equilibrium (HWE) was calculated for each SNP, and SNPs that deviated from HWE were noted but not excluded from the analysis. For the final set of 554,6261 SNPs, single SNP tests of association assuming an additive genetic model were conducted using PLINK in 183 cases and 519 controls of European ancestry. Tests of association were also performed adjusting for age and sex. We identified one SNP associated with diLQTS at p<7.0×10−8 on chromosome 9 (Odds ratio = 2.28; 95% CI: 1.69 –3.08). We also identified 4 other associations at a significance level of p<9.0×10−7 on chromosomes 9, 11, and 19 and 10 other associations at a significance level of p<9.0×10−6 on chromosomes 7, 9, 13, 19, 21. Of the 15 SNPs most significantly associated with diLQTS, only three were located within genes, none were near known miRNAs, and none were located in a candidate gene or region for diLQTS.
Conclusion We have identified potential novel genomic regions associated with diLQTS. Further studies are needed to replicate these findings and to determine the function of these new candidate regions to better define the role individual genetic variants have on the development of diLQTS.