Inhibition of Putative Ibrutinib Targets Promotes Atrial Fibrillation, Conduction Blocks, and Proarrhythmic Electrocardiogram Indices: A Mendelian Randomization Analysis
Hongxuan Xu
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (lead), Writing - original draft (lead), Writing - review & editing (equal)
Search for more papers by this authorBingxun Li
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Conceptualization (supporting), Formal analysis (equal), Investigation (equal), Writing - review & editing (equal)
Search for more papers by this authorPinchao Lv
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Data curation (equal), Investigation (equal), Project administration (equal)
Search for more papers by this authorYing Chen
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Project administration (equal)
Search for more papers by this authorYanyun Lin
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Project administration (supporting)
Search for more papers by this authorAn Zhang
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Project administration (supporting)
Search for more papers by this authorJing Zhao
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Investigation (supporting), Project administration (supporting)
Search for more papers by this authorGuoxiong Zhou
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Investigation (supporting)
Search for more papers by this authorCorresponding Author
Lin Wu
Department of Cardiology, Peking University First Hospital, Beijing, China
State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
Correspondence: Lin Wu ([email protected])
Contribution: Funding acquisition (lead), Supervision (lead), Validation (equal)
Search for more papers by this authorHongxuan Xu
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Investigation (lead), Methodology (lead), Writing - original draft (lead), Writing - review & editing (equal)
Search for more papers by this authorBingxun Li
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Conceptualization (supporting), Formal analysis (equal), Investigation (equal), Writing - review & editing (equal)
Search for more papers by this authorPinchao Lv
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Data curation (equal), Investigation (equal), Project administration (equal)
Search for more papers by this authorYing Chen
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Project administration (equal)
Search for more papers by this authorYanyun Lin
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Project administration (supporting)
Search for more papers by this authorAn Zhang
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Project administration (supporting)
Search for more papers by this authorJing Zhao
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Investigation (supporting), Project administration (supporting)
Search for more papers by this authorGuoxiong Zhou
Department of Cardiology, Peking University First Hospital, Beijing, China
Contribution: Investigation (supporting)
Search for more papers by this authorCorresponding Author
Lin Wu
Department of Cardiology, Peking University First Hospital, Beijing, China
State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
Correspondence: Lin Wu ([email protected])
Contribution: Funding acquisition (lead), Supervision (lead), Validation (equal)
Search for more papers by this authorHongxuan Xu, Bingxun Li, and Pinchao Lv contributed equally to this work and share the co-first authorship.
ABSTRACT
Background
The mechanism by which ibrutinib, a Bruton's tyrosine kinase inhibitor, can elevate the risk of arrhythmias is not fully elucidated. In this study, we explored how inhibition of off-target kinases can contribute to this phenomenon.
Methods
We performed a Mendelian randomization analysis to examine the causal associations between genetically proxied inhibition of six putative ibrutinib drug targets (ErbB2/HER2, CSK, JAK3, TEC, BLK, and PLCG2) and the atrial fibrillation (AF) risk, proarrhythmic ECG indices, and cardiometabolic traits and diseases. Inverse-variance weighted random-effects models and Wald ratio were used to examine the associations between genetically proxied inhibition of these drug targets and the risk of outcomes. Colocalization analyses were employed to examine the robustness of the causally significant findings. ELISAs were used to measure ErbB2 levels in intracardiac plasma samples.
Results
Genetically proxied ErbB2 inhibition was associated with an increased AF risk, higher P wave terminal force, and prolonged QTc interval. Patients with AF had significantly higher intracardiac ErbB2 levels compared with patients with paroxysmal supraventricular tachycardia. CSK inhibition prolonged the QRS duration, decreased the QTc interval, and was potentially linked to conduction blocks. PLCG2 inhibition led to decreased P wave terminal force, shorter QTc interval, and increased risk of left bundle branch block. BLK inhibition shortened the QTc interval and was also associated with atrioventricular block.
Conclusion
The off-target effects and downstream targets of ibrutinib, including CSK, PLCG2, ERBB2, TEC, and BLK, may lead to cardiac electrical homeostasis imbalances and lethal cardiovascular diseases. Using drugs that inhibit these targets should be given extra caution.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
Additional information on statistical analysis, imputation, and quality control measures are included in the respective publications. All data used in this study can be downloaded from the cited publications. GWAS summary data from UK Biobank can be accessed at: https://www.nealelab.is/uk-biobank. FinnGen: https://www.finngen.fi/en/access_results. Gtex eQTL: https://www.gtexportal.org/home/downloads/adult-gtex#qtl. Decode pQTL: https://www.decode.com/summarydata/. QTc interval: https://personal.broadinstitute.org/ryank/Nauffal_2022_QT_GWAS_SAIGE.zip. Summary GWAS data of P wave duration, P wave terminal force, PR interval, heart rate variability, and atrial fibrillation can be accessed at GWAS catalog under the ID (GCST004826, GCST004824, GCST010320, GCST004732, GCST004733, GCST004734, and GCST006414).
Supporting Information
| Filename | Description |
|---|---|
| cai270004-sup-0001-Additional_file_1-final_version-20250214.docx43.3 KB | Supporting information. |
| cai270004-sup-0002-Additional_file_2-final_version-20250214.docx75.5 KB | Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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