Post-Acute Sequelae of COVID-19 (PASC) is increasingly associated with long-term cardiovascular complications, yet the underlying molecular mechanisms, remain poorly understood. Host genetic susceptibility is likely to modulate post-viral cardiac vulnerability, but its interaction with persistent molecular remodelling after SARS-CoV-2 infection has not been systematically investigated. We employed an integrative multi-omics framework combining a pilot genome-wide association study (GWAS) of Indian PASC patients with post-acute cardiac transcriptomic profiling from a SARS-CoV-2-infected Golden Syrian hamster (GSH) model. GWAS signals were mapped to differentially expressed genes, followed by integrative stratification based on genetic risk and transcriptional perturbation. Consequences of genetic variations were quantified using structural bioinformatics approaches involving Molecular Dynamics. GWAS identified multiple loci associated with PASC, including genes implicated in arrhythmia, myocardial remodelling, vascular signaling, and cardiometabolic regulation. Integration with post-acute cardiac transcriptomics of GSH revealed 15 genes with convergent genetic and transcriptional evidence. Although no global monotonic correlation was observed between genetic risk and expression magnitude, genes segregated into distinct mechanistic classes, including genetically primed and virally activated drivers, inherited susceptibility genes with minimal post-viral expression change, and virus-driven transcriptional responses. Structural and molecular dynamics analyses of EYA2, TTN, VAV2, and KCNQ1 demonstrated variant-specific destabilization affecting myocardial stress adaptation, sarcomeric mechanics, vascular signalling, and cardiac electrical stability. These findings support a model where inherited genetic susceptibility interacts with persistent post-infectious cardiac remodelling to drive chronic cardiovascular dysfunction observed in PASC patients. Integrative host genomics provides a mechanistic framework for risk stratification and precision surveillance of post-COVID cardiovascular disease (CVD).
