A Common Ancestry-Specific Sodium Channel Variant Increases Susceptibility to Drug-Induced QTc Prolongation: Evidence From a Large Biobank

T he risk for QT prolongation and torsades de pointes after exposure to drugs that block the rapidly activating delayed rectifier potassium current ( IKr ) varies among patients, even accounting for clinical risk factors. This heterogeneity is attributed to genetic variation, including S1103Y, which is the most prevalent variant (minor allele frequency ≈ 12%) in the cardiac sodium channel gene ( SCN5A ) among individuals of African ancestry, but rare in individuals of European ancestry. 1 Patients carrying 1 S1103Y variant (S/Y) have higher risk of sudden infant death syndrome 1 and sudden cardiac death 2 than patients without variants (S/S). We previously demonstrated that S1103Y variant cardiomyocytes induced from pluripotent stem cells had baseline action potential durations similar to S/S cells but were hypersensitive to IKr blockade by dofetilide. There was no effect of S1103Y genotype on corrected QT (QTc) in 1479 patients without heart disease or QT-prolonging drug exposure. 3 Here, we report that S1103Y carrier status affects QTc at baseline and upon drug exposure in a larger cohort. BioVU, the Vanderbilt University Medical Center bio-bank, links genetic data with clinical records, including ECG and medication reconciliation. 4 Whole genome sequencing (WGS) was recently completed in 250 000 samples. We focus here on the first 34 523-sample cohort, which was enriched for participants of non-European ancestry. Patients with WGS passing