The impact of coronary heart disease-associated genetic variants on heart rate dynamics

Al Ashkar, Habib and Kharrat helu, Nihad and Kovács, Nóra and Túri, Gergő and Fiatal, Szilvia and Ádány, Róza and Pikó, Péter (2026) The impact of coronary heart disease-associated genetic variants on heart rate dynamics. HUMAN GENOMICS. ISSN 1473-9542 (In Press)

Preview

Text s40246-026-01035-5_reference.pdf - Published Version Available under License Creative Commons Attribution. Download (1MB) | Preview

Abstract

Background Exercise-induced heart rate response (ΔHR) reflects autonomic regulation and cardiovascular fitness. While coronary heart disease (CHD)-associated genetic variants are known to influence vascular and metabolic pathways, their role in modulating heart rate dynamics remains underexplored. This study aimed to evaluate and functionally characterize CHD-related genetic variants associated with ΔHR using integrated statistical, network-based, and regulatory approaches. Methods Sixteen CHD-linked single-nucleotide polymorphisms (SNPs) were analyzed in a Hungarian population-based cohort (n = 665) using adjusted linear regression models. YMCA 3 min step test was carried out, with HR measured at rest, immediately post-exercise, and during recovery at 5 and 10 min. An optimized genetic risk score (oGRS) was constructed through stepwise inclusion based on model performance. Functional clustering was performed using STRING network analysis, and regulatory potential was assessed via RegulomeDB. Results Four SNPs—rs6725887 (WDR12), rs964184 (ZPR1), rs9349379 (PHACTR1), and rs1746048 (CXCL12)—showed individually significant positive associations with ΔHR (p < 0.05). An additional four variants—rs646776 (CELSR2), rs46522 (UBE2Z), rs10455872 (LPA), and rs12190287 (TCF21)—were retained in the final oGRS based on incremental model improvement, yielding a cumulative p-value of 6.97 × 10⁻9. The oGRS was significantly associated with multiple heart rate parameters, including HRexerc, ΔHR5min, and ΔHR10min (Bonferroni-corrected p < 0.00625). STRING analysis identified a functional cluster comprising five genes (CELSR2, PHACTR1, UBE2Z, WDR12, and ZPR1), while CXCL12, LPA, and TCF21 remained unclustered, suggesting functional heterogeneity. All oGRS variants exhibited high regulatory potential (RegulomeDB ranks 1b–1f), with rs9349379 (PHACTR1) showing the highest transcriptional relevance (score 0.99). Conclusions These findings demonstrate that CHD-associated genetic variants significantly influence exercise-induced heart rate dynamics. The oGRS framework provides a reproducible approach for dissecting polygenic contributions to autonomic cardiovascular traits in a general population, with implications for functional genomics and personalized cardiovascular risk stratification.

Actions (login required)

View Item