TY - JOUR
T1 - Pharmacogenomic markers associated with drug-induced QT prolongation
T2 - a systematic review
AU - Bentestuen, Marlene Schouby
AU - Weis, Christian Noe
AU - Jeppesen, Caroline Bækmann
AU - Thiele, Liv Swea
AU - Thirstrup, Janne Pia
AU - Cordero-Solorzano, Juan
AU - Jensen, Henrik Kjærulf
AU - Starnawska, Anna
AU - Hauser, Alexander Sebastian
AU - Gasse, Christiane
PY - 2025
Y1 - 2025
N2 - AIM: 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.METHODS: 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.RESULTS: 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
-14). We also found an overlap between diQTP-associated genes and congenital long QT syndrome genes.
CONCLUSION: 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.REGISTRATION: A protocol was pre-registered at PROSPERO under registration number CRD42022296097.DATA DEPOSITION: Data sets generated by this review are available at figshare: DOI: 10.6084/m9.figshare.27959616.
AB - AIM: 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.METHODS: 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.RESULTS: 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
-14). We also found an overlap between diQTP-associated genes and congenital long QT syndrome genes.
CONCLUSION: 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.REGISTRATION: A protocol was pre-registered at PROSPERO under registration number CRD42022296097.DATA DEPOSITION: Data sets generated by this review are available at figshare: DOI: 10.6084/m9.figshare.27959616.
KW - Drug-induced QT prolongation
KW - cardiac safety
KW - drug safety
KW - drug-induced arrhythmia
KW - personalized medicine
KW - pharmacogenetics
KW - pharmacogenomics
UR - https://www.scopus.com/pages/publications/105000531242
U2 - 10.1080/14622416.2025.2481025
DO - 10.1080/14622416.2025.2481025
M3 - Review
C2 - 40116580
SN - 1462-2416
VL - 26
SP - 53
EP - 72
JO - Pharmacogenomics
JF - Pharmacogenomics
IS - 1-2
ER -