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From blood to heartbeat: Plasma proteins and Brugada syndrome revealed by Mendelian randomization.

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Title: From blood to heartbeat: Plasma proteins and Brugada syndrome revealed by Mendelian randomization.
Authors: Zhao Z; Zhejiang University School of Medicine, Hangzhou, China; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China., Cao B; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China., Guo H; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China., Li J; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China., Chen X; Zhejiang University School of Medicine, Hangzhou, China; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China. Electronic address: chxmin@hotmail.com.
Source: Heart rhythm [Heart Rhythm] 2026 Oct; Vol. 23 (10), pp. 2217-2228. Date of Electronic Publication: 2025 Oct 09.
Publication Type: Journal Article
Language: English
Journal Info: Publisher: Elsevier Country of Publication: United States NLM ID: 101200317 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1556-3871 (Electronic) Linking ISSN: 15475271 NLM ISO Abbreviation: Heart Rhythm Subsets: MEDLINE
Imprint Name(s): Original Publication: New York, NY : Elsevier, c2004-
MeSH Terms: Brugada Syndrome*/genetics , Brugada Syndrome*/blood , Brugada Syndrome*/physiopathology , Mendelian Randomization Analysis*/methods , Blood Proteins*/genetics , Blood Proteins*/metabolism , Heart Rate*/physiology, Finland/epidemiology ; Proteomics/methods ; Humans ; Electrocardiography ; Male ; Female
Abstract: Background: Brugada syndrome (BrS) is a hereditary arrhythmia characterized by distinctive electrocardiographic patterns and a high risk of sudden cardiac death. Although SCN5A mutations account for 20%-30% of cases, the majority remain unexplained. Recent evidence suggests plasma proteins may contribute to BrS pathogenesis through non-ion channel mechanisms, such as inflammation and metabolism, although causal roles are unclear.
Objective: The study aimed to assess the causal relationship between plasma proteins and BrS using Mendelian randomization (MR) and explore underlying molecular mechanisms.
Methods: Using pQTL proteomic data from a Finnish cohort, we evaluated causal associations between 4185 plasma proteins and BrS via MR. The inverse variance weighted (IVW) method served as the primary analysis, supported by additional MR methods and sensitivity tests to ensure robustness. MR-CAUSE was used to identify proteins with unique causal patterns. For significant proteins, we constructed protein-protein interaction (PPI) networks and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. A machine learning-based model integrated these results to prioritize candidate proteins.
Results: 20 plasma proteins were identified as potentially associated with BrS. Sensitivity analyses supported the robustness of these findings. HSPB1, MAPKAPK2, PDLIM4, and MMP1 emerged as top candidates based on causal strength, biological relevance, and network centrality.
Conclusion: This study provides insight into the molecular landscape of BrS and identifies high-priority plasma proteins for further investigation. Experimental and clinical validation is needed to evaluate their diagnostic and therapeutic potential.
(Copyright © 2025 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Disclosures The authors have no conflicts of interest to disclose.
Contributed Indexing: Keywords: Brugada syndrome; Cardiac electrophysiology; Genetic epidemiology; Mendelian randomization; Plasma proteins
Substance Nomenclature: 0 (Blood Proteins)
Entry Date(s): Date Created: 20251009 Date Completed: 20260925 Latest Revision: 20260925
Update Code: 20260926
DOI: 10.1016/j.hrthm.2025.09.039
PMID: 41067469
Database: MEDLINE
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  Data: From blood to heartbeat: Plasma proteins and Brugada syndrome revealed by Mendelian randomization.
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  Data: <searchLink fieldCode="AU" term="%22Zhao+Z%22">Zhao Z</searchLink>; Zhejiang University School of Medicine, Hangzhou, China; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China.<br /><searchLink fieldCode="AU" term="%22Cao+B%22">Cao B</searchLink>; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China.<br /><searchLink fieldCode="AU" term="%22Guo+H%22">Guo H</searchLink>; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China.<br /><searchLink fieldCode="AU" term="%22Li+J%22">Li J</searchLink>; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China.<br /><searchLink fieldCode="AU" term="%22Chen+X%22">Chen X</searchLink>; Zhejiang University School of Medicine, Hangzhou, China; Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China. Electronic address: chxmin@hotmail.com.
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  Data: <searchLink fieldCode="JN" term="%22101200317%22">Heart rhythm</searchLink> [Heart Rhythm] 2026 Oct; Vol. 23 (10), pp. 2217-2228. <i>Date of Electronic Publication: </i>2025 Oct 09.
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  Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Elsevier%22">Elsevier </searchLink><i>Country of Publication: </i>United States <i>NLM ID: </i>101200317 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>1556-3871 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2215475271%22">15475271 </searchLink><i>NLM ISO Abbreviation: </i>Heart Rhythm <i>Subsets: </i>MEDLINE
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  Data: <i>Original Publication</i>: New York, NY : Elsevier, c2004-
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  Data: <searchLink fieldCode="MM" term="%22Brugada+Syndrome%22">Brugada Syndrome*</searchLink>/<searchLink fieldCode="MM" term="%22Brugada+Syndrome+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Brugada+Syndrome%22">Brugada Syndrome*</searchLink>/<searchLink fieldCode="MM" term="%22Brugada+Syndrome+blood%22">blood</searchLink> <br /><searchLink fieldCode="MM" term="%22Brugada+Syndrome%22">Brugada Syndrome*</searchLink>/<searchLink fieldCode="MM" term="%22Brugada+Syndrome+physiopathology%22">physiopathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Mendelian+Randomization+Analysis%22">Mendelian Randomization Analysis*</searchLink>/<searchLink fieldCode="MM" term="%22Mendelian+Randomization+Analysis+methods%22">methods</searchLink> <br /><searchLink fieldCode="MM" term="%22Blood+Proteins%22">Blood Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Blood+Proteins+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Blood+Proteins%22">Blood Proteins*</searchLink>/<searchLink fieldCode="MM" term="%22Blood+Proteins+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Heart+Rate%22">Heart Rate*</searchLink>/<searchLink fieldCode="MM" term="%22Heart+Rate+physiology%22">physiology</searchLink><br /><searchLink fieldCode="MH" term="%22Finland%22">Finland</searchLink>/<searchLink fieldCode="MH" term="%22Finland+epidemiology%22">epidemiology</searchLink> ; <searchLink fieldCode="MH" term="%22Proteomics%22">Proteomics</searchLink>/<searchLink fieldCode="MH" term="%22Proteomics+methods%22">methods</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Electrocardiography%22">Electrocardiography</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Female%22">Female</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background: Brugada syndrome (BrS) is a hereditary arrhythmia characterized by distinctive electrocardiographic patterns and a high risk of sudden cardiac death. Although SCN5A mutations account for 20%-30% of cases, the majority remain unexplained. Recent evidence suggests plasma proteins may contribute to BrS pathogenesis through non-ion channel mechanisms, such as inflammation and metabolism, although causal roles are unclear.<br />Objective: The study aimed to assess the causal relationship between plasma proteins and BrS using Mendelian randomization (MR) and explore underlying molecular mechanisms.<br />Methods: Using pQTL proteomic data from a Finnish cohort, we evaluated causal associations between 4185 plasma proteins and BrS via MR. The inverse variance weighted (IVW) method served as the primary analysis, supported by additional MR methods and sensitivity tests to ensure robustness. MR-CAUSE was used to identify proteins with unique causal patterns. For significant proteins, we constructed protein-protein interaction (PPI) networks and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. A machine learning-based model integrated these results to prioritize candidate proteins.<br />Results: 20 plasma proteins were identified as potentially associated with BrS. Sensitivity analyses supported the robustness of these findings. HSPB1, MAPKAPK2, PDLIM4, and MMP1 emerged as top candidates based on causal strength, biological relevance, and network centrality.<br />Conclusion: This study provides insight into the molecular landscape of BrS and identifies high-priority plasma proteins for further investigation. Experimental and clinical validation is needed to evaluate their diagnostic and therapeutic potential.<br /> (Copyright © 2025 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)
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  Data: Disclosures The authors have no conflicts of interest to disclose.
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        Text: English
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        StartPage: 2217
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      – SubjectFull: Finland epidemiology
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