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

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. 1Patients 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. 3Here, we report that S1103Y carrier status affects QTc at baseline and upon drug exposure in a larger cohort.BioVU, the Vanderbilt University Medical Center biobank, links genetic data with clinical records, including ECG and medication reconciliation. 4Whole 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 quality control and at least 1 ECG were included.Children (age <18 years), nonsinus rhythm, and paced ECGs were excluded.Nonphysiologic ECG measurements were excluded.R-R, QRS, and QT values were drawn from those tabulated by reading cardiologists during their ECG clinical attestation.QTc was then computed using the Bazett formula.S1103Y genotypes and principal components of genetic ancestry were extracted from WGS data.QT-prolonging drug exposure was defined as 1 medication from a previously curated list 3 present in a medication reconciliation <48 hours before ECG.We excluded as-needed or intraoperative drugs due to dosage and administration frequency uncertainty.QTc was modeled as a function of S1103Y carrier status, drug exposure, age, sex, the first 5 principal components of genetic ancestry, R-R interval, and QRS interval using a multivariable linear regression.Genotype-drug and genotype-sex interactions were also included.Statistical analyses were performed in Julia; visualizations were created in Makie.jl.The Vanderbilt University Medical Center institutional review board approved this protocol.