| Title: | Multiomics Insights Into the Role of Spondin-1 in the Pathogenesis and Prognosis of Atrial Fibrillation. |
| Journal: | Journal of the American Heart Association |
| Published: | 23 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42333675/ |
| DOI: | https://doi.org/10.1161/jaha.126.050152 |
Publication 20562
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Abstract
BACKGROUND: Atrial fibrillation (AF) is characterized by progressive structural remodeling, yet molecular drivers remain incompletely understood. This study aimed to identify novel protein targets for AF using an integrative multiomics approach.</p>
METHODS: We performed a multilayered genetic screen combining Mendelian randomization and colocalization analyses of plasma protein (protein quantitative trait loci) and atrial expression quantitative trait loci with AF genome-wide association studies. SPON1 (spondin-1) was identified as a priority candidate and further characterized using single-nucleus RNA sequencing, spatial transcriptomics, and experimental validation. Clinical relevance was evaluated in the UK Biobank cohort by assessing associations with incident AF, cardiac magnetic resonance phenotypes, and long-term prognosis.</p>
RESULTS: The genetic screen identified SPON1 as a potential target for AF, supported by colocalization evidence across the plasma proteome (posterior probability of hypothesis 4=0.87) and atrial transcriptome (posterior probability of hypothesis 4=0.86). Single-cell and spatial transcriptomics revealed that SPON1 expression was specific to fibroblasts and enriched in extracellular matrix pathways. In the UK Biobank cohort (N=39 372), elevated plasma SPON1 levels were independently associated with an increased risk of incident AF (hazard ratio [HR], 1.17; P<0.001). Furthermore, high SPON1 levels were associated with increased left atrial volumes (P<0.05) and stratified the risk of heart failure and death (HR, 1.51; P<0.001) in patients with established AF. Experimental validation showed that recombinant SPON1 can induce a profibrotic phenotype in fibroblasts.</p>
CONCLUSIONS: In conclusion, this integrative study identifies SPON1 as a candidate with potential causal and prognostic relevance for AF. These findings suggest that targeting this protein may offer a strategy for modifying the structural substrate of AF.</p>
12 Keywords
- Atrial Fibrillation
- Extracellular Matrix Proteins
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Male
- Mendelian Randomization Analysis
- Multiomics
- Phenotype
- Prognosis
- Quantitative Trait Loci
8 Authors
- Xianglin Long
- Yeshen Zhang
- Xinyue Gao
- Hao Chen
- Yunshu Li
- Weiwu Xiong
- Xiaoyan Wang
- Zhihui Zhang
1 Application
| Application ID | Title |
|---|---|
| 1198847 | Integrated Associations of Polygenic Risk, Lifestyle Factors, and Cardiac Imaging Phenotypes with Atrial Fibrillation and Heart Failure: A Prospective Cohort Study |
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