Pharmacogenomic markers associated with drug-induced QT prolongation: a systematic review
Creators: name: Bentestuen, Marlene Schouby
name: Weis, Christian Noe
name: Jeppesen, Caroline Bækmann
name: Thiele, Liv Swea
name: Thirstrup, Janne Pia
name: Cordero-Solorzano, Juan
name: Jensen, Henrik Kjærulf
name: Starnawska, Anna
name: Hauser, Alexander Sebastian
name: Gasse, Christiane
Publisher: name: Taylor & Francis
Year: 2025
Subjects: subject: Medicine
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Environmental Sciences not elsewhere classified
subject: Biological Sciences not elsewhere classified
subject: Cancer
subject: Science Policy
subject: Infectious Diseases
subject: FOS: Health sciences

description: To systematically assess clinical studies involving patients undergoing drug therapy, comparing different genotypes to assess the relationship with changes in QT intervals, with no limitations on study design, setting, population, dosing regimens, or duration. This systematic review followed PRISMA guidelines and a pre-registered protocol. Clinical human studies on PGx markers of diQTP were identified, assessed using standardized tools, and categorized by design. Gene associations were classified as pharmacokinetic or pharmacodynamic. Identified genes underwent pathway enrichment analyses. Drugs were classified by third-level Anatomical Therapeutic Chemical (ATC) codes. Descriptive statistics were computed by study category and drug classes. Of 4,493 reports, 84 studies were included, identifying 213 unique variants across 42 drug classes, of which 10% were replicated. KCNE1-Asp85Asn was the most consistent variant. Most findings (82%) were derived from candidate gene studies, suggesting bias toward known markers. The diQTP-associated genes were mainly linked to “cardiac conduction” and “muscle contraction” pathways (false discovery rate = 4.71 × 10<sup>−14</sup>). We also found an overlap between diQTP-associated genes and congenital long QT syndrome genes. Key genes, drugs, and pathways were identified, but few consistent PGx markers emerged. Extensive, unbiased studies with diverse populations are crucial to advancing the field. A protocol was pre-registered at PROSPERO under registration number CRD42022296097. Data sets generated by this review are available at figshare: DOI: 10.6084/m9.figshare.27959616 Many commonly prescribed medicines can affect the heart’s electrical activity and cause a condition called QT prolongation. This condition increases the risk of irregular heart rhythms that may lead to cardiac arrest. Research suggests that genetic differences influence this risk, but no systematic review of the evidence has been done until now. We reviewed and assessed 84 clinical studies that looked at how genetic differences might affect QT prolongation in patients taking medicines. We found 213 unique genetic variants across 42 drug classes. Most studies focused on specific genes rather than the broader genome. Overall, only a few genetic variants showed consistent results across independent studies, and only one was identified in both candidate gene studies and studies examining the broader genome. Our findings indicate that we still do not fully understand the genetic risks of drug-induced QT prolongation. This suggests that researchers should conduct more comprehensive studies examining the whole genome in diverse populations to understand better who is at risk.