International journal of biological macromolecules · 2026
Common potential drug targets for ischemic stroke and coronary heart disease: CYR61, IL2RB, and ST3GAL2 are identified as key regulatory proteins.
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Chen Miao, Liu Zongni, Lou Inmaculada Xu, Wan Haitong, Zhou Huifen
Аннотация
BACKGROUND: Coronary heart disease (CHD) and ischemic stroke (IS) frequently co-occur; however, their shared molecular drivers remain poorly understood, limiting the development of dual-indication therapies. This study aims to characterize the bidirectional genetic relationship between CHD and IS and to prioritize shared candidate proteins as potential therapeutic targets or biomarkers.
METHODS: Bidirectional two-sample Mendelian randomization (MR) was performed using GWAS summary statistics, with inverse-variance weighting as the primary analysis method. To resolve conceptual ambiguity regarding protein roles, we integrated MR and colocalization analyses across CHD, IS, and plasma proteomic QTLs to identify proteins driven by shared genetic signals. Candidate proteins were further contextualized using single-cell transcriptomics, followed by drug-repurposing predictions and exploratory molecular dynamics (MD) simulations. In vivo experiments were conducted to provide expression-level validation of prioritized candidates in disease models.
RESULTS: IVW MR supported a bidirectional association between IS and CHD (OR = 1.307, 95% CI 1.096-1.560, P = 0.003). Integrative analyses prioritized CYR61, IL2RB, and ST3GAL2 as shared candidate proteins. While MD simulations generated structural hypotheses regarding drug-protein interactions, in vivo experiments confirmed significant differential expression of these candidates, supporting their clinical relevance at the expression level.
CONCLUSION: This integrative genomics framework clarifies the shared genetic architecture of IS and CHD and identifies high-priority protein candidates for future functional and pharmacological validation.
METHODS: Bidirectional two-sample Mendelian randomization (MR) was performed using GWAS summary statistics, with inverse-variance weighting as the primary analysis method. To resolve conceptual ambiguity regarding protein roles, we integrated MR and colocalization analyses across CHD, IS, and plasma proteomic QTLs to identify proteins driven by shared genetic signals. Candidate proteins were further contextualized using single-cell transcriptomics, followed by drug-repurposing predictions and exploratory molecular dynamics (MD) simulations. In vivo experiments were conducted to provide expression-level validation of prioritized candidates in disease models.
RESULTS: IVW MR supported a bidirectional association between IS and CHD (OR = 1.307, 95% CI 1.096-1.560, P = 0.003). Integrative analyses prioritized CYR61, IL2RB, and ST3GAL2 as shared candidate proteins. While MD simulations generated structural hypotheses regarding drug-protein interactions, in vivo experiments confirmed significant differential expression of these candidates, supporting their clinical relevance at the expression level.
CONCLUSION: This integrative genomics framework clarifies the shared genetic architecture of IS and CHD and identifies high-priority protein candidates for future functional and pharmacological validation.