| Title: | Plasma Proteomic Insights for Identification of Novel Predictors and Potential Drug Targets in Atrial Fibrillation: A Prospective Cohort Study and Mendelian Randomization Analysis |
| Journal: | Circulation Arrhythmia and Electrophysiology |
| Published: | 2 Oct 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39355913/ |
| DOI: | https://doi.org/10.1161/circep.124.013037 |
Publication 13291
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Abstract
BACKGROUND: Currently, there are no reliable methods for predicting and preventing atrial fibrillation (AF) in its early stages. This study aimed to identify plasma proteins associated with AF to discover biomarkers and potential drug targets.</p>
METHODS: The UK Biobank Pharma Proteomics Project examined 2923 circulating proteins using the Olink platform, forming the basis of this prospective cohort study. The UK Biobank Pharma Proteomics Project included a randomly selected discovery cohort and the consortium-selected replication cohort. The study's end point was incident AF, identified using International Classification of Diseases, Tenth Revision codes. The association between plasma proteins and incident AF was evaluated using Cox proportional hazard models in both cohorts. Proteins present in both cohorts underwent Mendelian randomization analysis to delineate causal connections, utilizing cis-protein quantitative trait loci as genetic tools. The predictive efficacy of the identified proteins for AF was assessed using the area under the receiver operating characteristic curve, and their druggability was explored.</p>
RESULTS: Data from 38 784 participants were included in this study. Incident AF cases were identified in the discovery cohort (1894; 5.5%) within a median follow-up of 14.5 years and in the replication cohort (451; 10.6%) within a median follow-up of 14.4 years. Twenty-one proteins linked to AF were identified in both cohorts. Specifically, COL4A1 (collagen IV α-1; odds ratio, 1.11 [95% CI, 1.04-1.19]; false discovery rate, 0.016) and RET (proto-oncogene tyrosine-protein kinase receptor Ret; odds ratio, 0.96 [95% CI, 0.94-0.98]; false discovery rate, 0.013) demonstrated a causal link with AF, and RET is druggable. COL4A1 improved the short- and long-term predictive performance of established AF models, as evidenced by significant enhancements in the area under the receiver operating characteristic, integrated discrimination improvement, and net reclassification index, all with P values below 0.05.</p>
CONCLUSIONS: COL4A1 and RET are associated with the development of AF. RET is identified as a potential drug target for AF prevention, while COL4A1 serves as a biomarker for AF prediction. Future studies are needed to evaluate the effectiveness of targeting these proteins to reduce AF risk.</p>
18 Keywords
- Aged
- Anti-Arrhythmia Agents
- Atrial Fibrillation
- Biomarkers
- Blood Proteins
- Female
- Humans
- Incidence
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Predictive Value of Tests
- Prospective Studies
- Proteomics
- Proto-Oncogene Mas
- Risk Assessment
- Risk Factors
- United Kingdom
10 Authors
- Xiaodong Peng
- Yukun Li
- Nian Liu
- Shijun Xia
- Xin Li
- Yiwei Lai
- Liu He
- Caihua Sang
- Jianzeng Dong
- Changsheng Ma
1 Application
| Application ID | Title |
|---|---|
| 103736 | Metabolism and imaging phenotypes in the prevention and treatment of cardiac arrhythmia and heart failure |
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