Genetic variation in RYR1 is associated with heart failure progression and mortality in a diverse patient population.

Introduction: Heart failure (HF) is a highly prevalent disease affecting roughly 7 million Americans. A transcriptome-wide analysis revealed upregulation in HF patients with severe pulmonary hypertension. Therefore, we aimed to further characterize the role of in HF progression and mortality.

Methods: In a mouse model of HF, expression of was compared in cardiac pulmonary, and vascular tissue between HF and control mice. Candidate single nucleotide polymorphisms (SNPs) in the gene region were identified, including variants affecting expression in relevant tissue types. A Cox proportional hazard model was used to analyze genetic associations of candidate SNPs with all-cause mortality in HF patients. An exploratory analysis assessed significantly associated SNPs with risk of HF and arrhythmia development.

Results: In the preclinical HF model, left ventricular expression of was increased compared to control (fold change = 2.08;  = 0.01). In 327 HF patients, decreased mortality risk was associated with two SNPs: rs12974674 (HR: 0.59; 95% CI: 0.40-0.87;  = 0.007) and rs2915950 (HR: 0.62, 95% CI: 0.43-0.88;  = 0.008). Based on eQTL data, these SNPs were associated with decreased expression in vascular tissue. Two missense variants, in linkage disequilibrium with rs2915950 (rs2915952 and rs2071089) were significantly associated with decreased mortality risk ( = 0.03) and decreased risk of atrial fibrillation/flutter (OR: 0.66, 95% CI: 0.44-0.96;  = 0.03 and OR: 0.67, 95% CI: 0.45-0.98;  = 0.04, respectively). Survival associations with these SNPs were replicated in HF patients self-identifying as Black in the UK Biobank, and the arrhythmia associations were replicated in the overall UK Biobank population.

Conclusion: Increased expression may contribute to HF progression, potentially through the mechanisms associated with calcium handling and arrhythmia development. Our findings suggest that should be further studied as a potential therapeutic target for reducing HF-related mortality.