Bentestuen Marlene Schouby, Weis Christian Noe, Jeppesen Caroline Bækmann, Thiele Liv Swea, Thirstrup Janne Pia, Cordero-Solorzano Juan, Jensen Henrik Kjærulf, Starnawska Anna, Hauser Alexander Sebastian, Gasse Christiane
Psychosis Research Unit, Aarhus University Hospital Psychiatry, Aarhus, Denmark.
Department of Clinical Medicine, Health, Aarhus University, Aarhus, Denmark.
Pharmacogenomics. 2025 Jan-Feb;26(1-2):53-72. doi: 10.1080/14622416.2025.2481025. Epub 2025 Mar 21.
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). 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.
系统评估涉及药物治疗患者的临床研究，比较不同基因型以评估与QT间期变化的关系，研究设计、研究地点、人群、给药方案或持续时间均无限制。
本系统评价遵循PRISMA指南和预先注册的方案。识别关于药物诱导的QT间期延长（diQTP）的药物基因组学（PGx）标志物的临床人体研究，使用标准化工具进行评估，并按设计分类。基因关联被分类为药代动力学或药效动力学。对鉴定出的基因进行通路富集分析。药物按解剖学治疗学化学（ATC）三级代码分类。按研究类别和药物类别计算描述性统计数据。
在4493篇报告中，纳入了84项研究，确定了42类药物中的213个独特变异，其中10%得到了重复验证。KCNE1-Asp85Asn是最一致的变异。大多数研究结果（82%）来自候选基因研究，表明对已知标志物存在偏倚。与diQTP相关的基因主要与“心脏传导”和“肌肉收缩”通路相关（错误发现率 = 4.71×10）。我们还发现diQTP相关基因与先天性长QT综合征基因之间存在重叠。
确定了关键基因、药物和通路，但出现的一致的PGx标志物很少。开展广泛、无偏倚的不同人群研究对推动该领域发展至关重要。
一项方案已在PROSPERO上预先注册，注册号为CRD42022296097。
本综述生成的数据集可在figshare上获取：DOI: 10.6084/m9.figshare.27959616。
