The F2RL1 rs1529505 PAR2 variant is linked to 16% higher HF-related mortality and increased adverse cardiac remodeling and inflammation in heart failure patients.
Do genetic variants linked to increased PAR2 expression increase the risk of adverse cardiac remodeling and heart failure-related mortality?
Genetic variants linked to increased PAR2 expression are associated with adverse cardiac remodeling, inflammation, and elevated HF-related mortality, highlighting PAR2 as a potential prognostic marker and therapeutic target.
Absolute Event Rate: 0% vs 0%
Abstract Background and Aims Functional inhibition of protease-activated receptor 2 (PAR2) via inhibition of its substrate FXa has been shown to reduce adverse clinical outcomes in various HF subgroups, though the mechanism remains unclear. This study aims to conduct a comprehensive translational investigation of the role of PAR2 in HF. Methods We conducted a biopsy study in HF patients without underlying conditions (n=84) using transvascular right ventricular endomyocardial biopsy (EMB). An exploratory genetic analysis of the HERMES HF cohort (n=583,167) identified F2RL1 (PAR2) variants associated with HF, and the UK Biobank HF cohort (n=18,239) was used to assess the relationship between HF-related mortality and the F2RL1 variant most strongly linked to its expression. Mechanistic studies included ApoE−/− and ApoE−/− PAR2−/− mice on a C57Bl/6 background fed a Western diet (21% fat, 0.15% cholesterol) for four months starting at eight weeks of age. Findings The biopsy study demonstrated that cardiac PAR2 upregulation correlates with increased complement C3 expression, higher NT-proBNP levels, and adverse cardiac remodeling on echocardiography, reinforcing its role in HF progression. Genetic analysis identified a strong association between F2RL1 expression and HF, with rs1529505 emerging as the most robustly linked variant. In the UK Biobank cohort (n = 20,650), rs1529505 was associated with a 16% increased risk of HF-related mortality (OR = 1.16 1.02-1.32, p = 0.025). Experimental models confirmed a protective effect of PAR2 deficiency, leading to reduced cardiac inflammation (reduced IL-6 and C3) and remodeling markers. Interpretation Genetic variants linked to increased PAR2 expression were associated with adverse cardiac remodeling, heightened cardiac inflammation, and elevated HF-related mortality. Notably, the rs1529505 variant emerges as a promising prognostic marker and therapeutic target, potentially paving the way for personalized treatment strategies in HF management.
Ghanbari et al. (Sat,) reported a other. The F2RL1 rs1529505 PAR2 variant is linked to 16% higher HF-related mortality and increased adverse cardiac remodeling and inflammation in heart failure patients.