AI Article Synopsis
- The study aimed to explore the relationship between plasma proteins and various electrocardiogram (ECG) traits to enhance understanding of cardiac conduction and its implications for arrhythmias.
- Researchers utilized a Mendelian randomization approach to identify specific proteins linked to ECG traits such as P wave duration, PR interval, and others, confirming their findings through several analytical methods.
- The analysis revealed several proteins associated with different ECG attributes, and some were identified as potential drug targets, indicating that these proteins may play a role in managing cardiac conduction disorders.
Article Abstract
Background: Cardiac conduction disorders predispose individuals to arrhythmias, currently but the exact mechanisms of cardiac conduction remain elusive. The study sought to identify the causal association between circulating plasma proteins and electrocardiogram (ECG) traits, offer valuable biological insights and clinical guidance into cardiac conduction.
Methods: Proteome-wide Mendelian randomization (MR) analysis was firstly conducted to assess causal associations between plasma proteins and five ECG traits, including P wave duration (PWD), QRS duration, PR, QT and RR intervals. Multiple sensitivity analyses were implemented. The reverse MR analysis, colocalization analysis and replication analysis were used to consolidate the reliability of our results. Then, we conducted mediation analysis to explore potential mechanism between plasma proteins and ECG traits. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were applied to clarify the biological functions of target proteins. Finally, phenome-wide MR (Phe-MR) and drug databases were searched.
Results: We identified 3 proteins (FAM151A, VEGF165, VEGF121) associated with PWD, 12 proteins (ABHD10, ADK, Cathepsin_S, DUSP13, Ephrin_A3, MAPRE2, OMG, PAM, PMM1, SH3BGRL3, TCP4, SYT11) linked to PR interval, 1 protein (PKC_A) related to QRS duration, and 2 proteins (MXRA7, SVEP1) associated with QT interval. A significant causal effects of ECG traits on them was not found in reverse MR. Colocalization and replication analyses strengthened our findings further. The impacts were partly mediated by anthropometric measures. Enrichment analysis of target proteins mainly enriched for multiple key pathways such as regulation of hydrolase activity and fibronectin binding. Through drug databases searching, 5 identified proteins (VEGFA, ADK, PAM, Cathepsin_S, PKC_A) were considered druggable.
Conclusions: We discovered significant causal associations between genetically predicted levels of 18 plasma proteins and ECG traits. These results highlight the importance of circulating plasma proteins in cardiac conduction and open up the possibility of novel arrhythmia drug development.
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| http://dx.doi.org/10.1016/j.intimp.2024.113520 | DOI Listing |
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