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Published on: May 4, 2015
Mendelian randomization reveals plasminogen as a common therapeutic target for myocardial infarction and atrial
Hadi Charati1,2, Ahmad Hamta1
1Department of Biology, Faculty of Sciences, Arak University, Arak, Iran.
Insights
This study identified shared causal plasma proteins for myocardial infarction (MI) and atrial fibrillation (AF), revealing plasminogen (PLG) as a common protective factor. These findings offer new therapeutic targets for cardiovascular disease (CVD).
Area of Science:
- Genetics and Cardiovascular Disease Research
- Biomarker Discovery in Cardiology
- Proteomics and Disease Causality
Background:
- Plasma proteins are crucial in myocardial infarction (MI) and atrial fibrillation (AF).
- The shared causal links between plasma proteins and these two cardiovascular conditions remain largely unexplored.
- Understanding these connections is vital for developing effective treatments.
Purpose of the Study:
- To investigate the causal roles of plasma proteins in myocardial infarction (MI) and atrial fibrillation (AF).
- To identify shared causal plasma proteins between MI and AF.
- To explore potential therapeutic strategies targeting these shared proteins.
Main Methods:
- Utilized cis-protein quantitative trait loci (cis-pQTLs) for 4,719 plasma proteins.
- Employed two-sample Mendelian randomization (MR) to assess causality.
- Performed multi-trait MR and Phenome-Wide Association Studies (PheWAS) for comprehensive analysis.
Main Results:
- Identified 21 and 9 causal plasma proteins for MI and AF, respectively.
- Plasminogen (PLG) emerged as a common protective factor for both MI and AF, also showing protective effects against coronary atherosclerosis.
- Six cis-pQTLs, including PLG, PCSK9, and ITIH4, were associated with both MI and AF, with evidence of interactions among causal proteins.
Conclusions:
- Established causal inference for human plasma proteins in MI and AF.
- Highlighted the pleiotropic effects of identified proteins and sNPs on cardiometabolic phenotypes, underscoring their role in cardiovascular disease (CVD) pathology.
- Provided novel insights into shared causality and potential common therapeutic drugs, such as PLG activators, for MI and AF.
Introduction:
Plasma proteins play essential roles in myocardial infarction (MI) and atrial fibrillation (AF); however, it remains unknown whether the two disorders share causal plasma proteins.
Methods:
The present study utilizes cis-protein quantitative trait loci (cis-pQTLs) for 4,719 plasma proteins to assess their causality on MI and AF.
Results:
Two-sample Mendelian randomization (MR) identifies 21 and 9 plasma proteins for MI and AF, respectively (FDR P<0.05), with plasminogen (PLG) being a commonly protective factor against both diseases. Multi-trait MR suggests that PLG is also protective against coronary atherosclerosis. PheWAS analysis identifies associations of six cis-pQTLs with both MI and AF, i.e., rs11751347 (PLG), rs11591147 (PCSK9), rs77347777 (ITIH4), rs936228 (ULK3), rs2261033 (AIF1V), and rs2711897 (BDH2). Furthermore, interactions exist among the causal plasma proteins, with PLG directly interacting with multiple others. Drug-gene databases suggest that PLG activators, such as Urokinase, Reteplase, Streptokinase, Alteplase, Anistreplase, Tenecteplase, Desmoteplase, and Defibrotide sodium may serve as common therapeutic drugs for MI and AF.
Conclusion:
Our study provides a causal inference of human plasma proteins in MI and AF. Several of the identified proteins and single nucleotide polymorphisms (sNPs) exert pleiotropic effects on other cardiometabolic phenotypes, indicating their crucial roles in the pathology of cardiovascular disease (CVD). Our study provides new insights into the shared causality and drugs for MI and AF.
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