Common Ancestry-Specific Ion Channel Variants Predispose to Drug-Induced Arrhythmias

Multiple reports associate the cardiac sodium channel gene (SCN5A) variants S1103Y and R1193Q with type 3 congenital long QT syndrome and drug-induced long QT syndrome. These variants are too common in ancestral populations to be highly arrhythmogenic at baseline, however: S1103Y allele frequency is 8.1% in African Americans and R1193Q 6.1% in East Asians. R1193Q is known to increase late sodium current (I_Na-L) in cardiomyocytes derived from induced pluripotent stem cells but the role of these variants in modulating repolarization remains poorly understood.

We determined the effect of S1103Y on QT intervals among African-American participants in a large electronic health record. Using cardiomyocytes derived from induced pluripotent stem cells carrying naturally occurring or genome-edited variants, we studied action potential durations (APDs) at baseline and after challenge with the repolarizing potassium current (I_Kr) blocker dofetilide and I_Na-L and I_Kr at baseline.

In 1479 African-American participants with no confounding medications or diagnoses of heart disease, QT intervals in S1103Y carriers was no different from that in noncarriers. Baseline APD was no different in cells expressing the Y allele (SY, YY cells) compared with isogenic cells with the reference allele (SS cells). However, I_Na-L was increased in SY and YY cells and the I_Na-L blocker GS967 shortened APD in SY/YY but not SS cells (P<0.001). I_Kr was increased almost 2-fold in SY/YY cells compared with SS cells (tail current: 0.66±0.1 versus 1.2±0.1 pA/pF; P<0.001). Dofetilide challenge prolonged APD at much lower concentrations in SY (4.1 nmol/L [interquartile range, 1.5-9.3]; n=11) and YY (4.2 nmol/L [1.7-5.0]; n=5) than in SS cells (249 nmol/L [22.3-2905]; n=14; P<0.001 and P<0.01, respectively) and elicited afterdepolarizations in 8/16 SY/YY cells but only in 1/14 SS cells. R1193Q cells similarly displayed no difference in baseline APD but increased I_Kr and increased dofetilide sensitivity.

These common ancestry-specific variants do not affect baseline repolarization, despite generating increased I_Na-L. We propose that increased I_Kr serves to maintain normal repolarization but increases the risk of manifest QT prolongation with I_Kr block in variant carriers. Our findings emphasize the need for inclusion of diverse populations in the study of adverse drug reactions.