Genetic and Epigenetic Regulation of Inflammatory Genes Drives Calcific Aortic Valve Disease (CAVD)
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Introduction
Calcific aortic valve disease (CAVD) is the most common valvular disorder in older adults, characterized by progressive fibrosis, calcification, and impaired blood flow. Despite its growing burden, no effective pharmacological treatments exist. Inflammation and epigenetic dysregulation are increasingly recognized as central to CAVD pathogenesis. This study aimed to identify key inflammatory genes and regulatory mechanisms contributing to disease development.
Methods
We performed a meta-analysis of aortic valve transcriptomic datasets, focusing on inflammation-related genes, to identify differentially expressed genes (DEGs) in CAVD. Blood-derived expression quantitative trait loci (eQTL) and DNA methylation QTL (mQTL) data were integrated with CAVD genome-wide association study (GWAS) results (FinnGen database) using a three-step summary data-based Mendelian randomization (SMR) framework. Additionally, we combined aortic eQTL data and inflammatory mediator GWAS to assess tissue-specific regulatory interactions through SMR and co-localization analyses.
Results
Fifty-seven inflammation-related DEGs were identified, enriched in immune cells from patients with CAVD. Multi-omics integration prioritized nine causal genes in blood, including PPARG, TLR2, LTA, TNF, C4A, IL6, RELA, C3, and TGFβ1. Among these, TNF and TGFβ1 were strongly associated with increased CAVD risk. In aortic tissue, SMR and co-localization analyses revealed TLR2, C4A, and AGER as key genes linked to inflammatory pathways, highlighting a potential gene-immune axis in disease progression.
Conclusions
Our integrative multi-omics analysis reveals that calcific aortic valve disease (CAVD) is driven by genetically and epigenetically regulated inflammatory pathways. We identify TNF and TGFβ1 as epigenetically controlled causal drivers, while AGER, C4A, and TLR2 emerge as tissue-specific mediators of aortic inflammation. These findings establish a causal link between immune dysregulation and CAVD pathogenesis, highlighting promising targets for biomarker development and precision therapies aimed at interrupting disease progression.
