Whole-exome sequencing reveals microsatellite DNA markers for response to dofetilide initiation in patients with persistent atrial fibrillation: A pilot study.

BACKGROUND

Dofetilide is a class III antiarrhythmic drug effective for the treatment of atrial fibrillation (AF). Dofetilide initiation (DI) associates with corrected QT interval (QTc) prolongation. Significant QTc prolongation during DI mandates dose adjustment or discontinuation of the drug. Microsatellite DNA are novel genetic markers associated with congenital and acquired health conditions.

HYPOTHESIS

DNA microsatellite polymorphism may associate with QTc response to dofetilide initiation in patients with persistent AF.

METHODS

We performed whole-exome sequencing in a cohort of patients with persistent AF undergoing DI. Electrocardiographic variables and clinical data were assessed. We defined patients as eligible for DI when no significant QTc prolongation (>20% compared with baseline) was seen with a 500-μg dose. We defined patients as ineligible for DI when significant QTc prolongation was seen during DI with 500 μg. We investigated polymorphisms for 11 919 DNA microsatellite loci in relation to QTc response to DI.

RESULTS

During the study, 14 consecutive patients with persistent AF presenting for DI were enrolled. Whole-exome sequencing revealed 14 different microsatellite loci in the 2 groups. All genes or proximal genes that harbor these loci are known to have expression in the human heart. Two genes, MYH6 and TRAK2, are known to have expression in the atria. TRAK2 is known to interact with KCNJ2, the inward-rectifier potassium channel 1.

CONCLUSIONS

Microsatellite DNA polymorphisms seem to associate with QTc response to DI therapy in patients with persistent AF who are deemed otherwise eligible for dofetilide therapy.