Genetic Variation in RYR1 is Associated with Heart Failure Progression and Mortality in a Diverse Patient Population

Leonardo Armando Guerra Christelle Lteif Yimei Huang Rylie M Flohr Alejandra C Nogueira Brian Gawronski Julio Duarte ^*

• University of Florida, Gainesville, United States

Introduction: Heart failure (HF) is a highly prevalent disease affecting roughly 7 million Americans. A transcriptome-wide analysis revealed RYR1 upregulation in HF patients with severe pulmonary hypertension. Therefore, we aimed to further characterize the role of RYR1 in HF progression and mortality.Methods: In a mouse model of HF, expression of Ryr1 was compared in cardiac pulmonary, and vascular tissue between HF and control mice. Candidate single nucleotide polymorphisms (SNPs) in the RYR1 gene region were identified, including variants affecting RYR1 expression for RYR1 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 Ryr1 was increased compared to control (fold change = 2.08; P = 0.01). In 327 HF patients, decreased mortality risk was associated with two RYR1 SNPs: rs12974674 (HR: 0.59; 95% CI: 0.40 – 0.87; P = 0.007) and rs2915950 (HR: 0.62, 95% CI: 0.43 – 0.88; P = 0.008). Based on eQTL data, these SNPs were associated with decreased RYR1 expression in vascular tissue. Two missense variants, in linkage disequilibrium with rs2915950 (rs2915952 and rs2071089) were significantly associated with decreased mortality risk (P = 0.03) and decreased risk of atrial fibrillation/flutter (OR: 0.66, 95% CI: 0.44 – 0.96; P = 0.03 and OR: 0.67, 95% CI: 0.45 – 0.98; P = 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 RYR1 expression may contribute to HF progression, potentially through the mechanisms associated with calcium handling and arrhythmia development. Our findings suggest that RYR1 should be further studied as a potential therapeutic target for reducing HF-related mortality.