Genetic risk factors for drug-induced long QT syndrome: findings from a large real-world case–control study

Abstract

Aim: Drug-induced long QT syndrome (diLQTS), an adverse effect of many drugs, can lead to sudden cardiac death. Candidate genetic variants in cardiac ion channels have been associated with diLQTS, but several limitations of previous studies hamper clinical utility. Materials & methods: Thus, the purpose of this study was to assess the associations of KCNE1-D85N, KCNE2-I57T and SCN5A-G615E with diLQTS in a large observational case–control study (6,083 self-reported white patients treated with 27 different high-risk QT-prolonging medications; 12.0% with diLQTS). Results: KCNE1-D85N significantly associated with diLQTS (adjusted odds ratio: 2.24 [95% CI: 1.35–3.58]; p = 0.001). Given low minor allele frequencies, the study had insufficient power to analyze KCNE2-I57T and SCN5A-G615E. Conclusion: KCNE1-D85N is a risk factor for diLQTS that should be considered in future clinical practice guidelines.

Plain Language Summary

Some medications can lead to a condition called drug-induced long QT syndrome (diLQTS), which can be a serious abnormal heart rhythm in some patients. In our research, we explored three specific changes in DNA related to the electrical function of the heart (KCNE1-D85N, KCNE2-I57T, SCN5A-G615E) and their link to diLQTS. Our study revealed a connection between KCNE1-D85N and diLQTS. This study emphasized the importance of including KCNE1-D85N in the medical guidelines to help identify patients at risk of diLQTS. We were unable to identify the connection of KCNE2-I57T and SCN5A-G615E with diLQTS, due to a low number of carriers in the study.

Keywords: :

• arrhythmia
• drug-induced long QT syndrome
• KCNE1-D85N
• pharmacogenomics
• torsade de pointes

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/pgs-2023-0229

Author contributions

AI Lopez-Medina: conception and design of the work, data analysis, interpretation of data for the work and drafting the work. AM Campos-Staffico: drafting the work, interpretation of data for the work and revising it critically for important intellectual content. CA A Chahal: interpretation of data for the work and revising it critically for important intellectual content. I Volkers: acquisition of data for the work and revising it critically for important intellectual content. JP Jacoby: acquisition of data for the work and revising it critically for important intellectual content. O Berenfeld: interpretation of data for the work and revising it critically for important intellectual content revising it critically for important intellectual content. JA Luzum: conception and design of the work, interpretation of data, drafting the work and revising it critically for important intellectual content.

Financial disclosure

This research was funded by the following sources: T32 TR004371/NIH CTSA/United States; K08 HL146990/HL/NHLBI NIH HHS/United States; F32 HL162231/NIHLBI/United States; W81XWH-18-2-0038/Department of Defense Grant/United States; R21-HL153694 NIH/United States; R21-EB032661 NIH/United States; and R01-HL156961 NIH/United States.

Competing interests disclosure

J. Luzum is a consultant for Ariel Precision Medicine. O. Berenfeld is a co-founder of Cor-Dx LLC. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval with a waiver of informed consent and have followed the principles outlined in the Declaration of Helsinki for all human investigations.