Shared genetic architecture of HCM and AF: Elevated NPPA/ANP is linked to atrial electrical remodeling

Hypertrophic cardiomyopathy (HCM) patients exhibit heightened susceptibility to atrial fibrillation (AF), yet the underlying genetic nexus remains poorly defined. This study aimed to identify genes common to HCM and AF, thereby revealing the underlying pathogenesis of susceptibility to AF in HCM patients.

Genes associated with HCM and AF were sourced from the Gene Expression Omnibus (GEO), Online Mendelian Inheritance in Man (OMIM), Comparative Toxicogenomics Database (CTD), GeneCards, and DisGeNET databases. We conducted a comparative analysis to identify overlapping genes between HCM and AF for further investigation, which included functional enrichment analysis, protein-protein interaction networks, and immune infiltration assessment. Key hub genes were determined using cytoHubba, a Cytoscape plugin, and their validation was performed using independent datasets GSE36961 and GSE115574. The genes corroborated by these datasets were additionally validated in clinical samples.

A total of 11 overlapping genes were identified between HCM and AF. Functional enrichment and immune infiltration analyses revealed their involvement in immune regulation and inflammatory processes. Three hub genes NPPA, ACE, and POMC were recognized as key molecular links between HCM and AF. Validation using the GSE36961 dataset confirmed the upregulation of NPPA in HCM, supporting its potential as a central gene connecting the two conditions. Consistent with the bioinformatics findings, exploratory clinical verification findings of serum levels of N-terminal fragment of A-type natriuretic peptide (NT-proANP), encoded by NPPA, were markedly elevated in both the HCM and HCM with AF groups compared with healthy controls (P < 0.01). Moreover, NT-proANP concentrations were significantly higher in the HCM + AF group than in the HCM-only group (P < 0.01).

This study identifies a shared genetic link between HCM and AF. The findings strongly associate elevated NT-proANP levels, encoded by the NPPA gene, with AF in HCM patients. We propose NT-proANP as a promising circulating biomarker for stratifying AF risk in this patient population.