LAUSR

AIMS Observational studies indicate that serum urate level is associated with heart failure. However, whether this association is causal remains controversial, due to confounding factors and reverse causality. We aim to evaluate the causal relationship of genetically predicted serum urate level with heart failure (HF). METHODS A bidirectional Mendelian randomisation (MR) study was performed. Instrumental variables were obtained from the largest genome-wide association studies of serum urate (457,690 individuals) to date. We obtained summary statistics of HF from HERMES consortium (47,309 cases; 930,014 controls), the FinnGen study (13,087 cases; 195,091 controls), and the UK Biobank study (1,088 cases; 360,106 controls). Inverse-variance weighted method was applied to obtain MR estimates and other statistical methods were conducted in the sensitivity analyses. The reverse MR analysis was performed to evaluate the effect of HF on serum urate levels. RESULTS Genetically determined serum urate level was associated with HF (odds ratio (OR), 1.07; 95% CI, 1.03-1.10; p=8.6×10-5). The main results kept robust in the most sensitivity analyses. The association pattern remained for the heart failure in FinnGen (OR, 1.10; 95%CI, 1.03-1.19; p=0.008) and the combined results of three data sources (OR, 1.08; 95%CI, 1.04-1.13; p<0.001). No consistent evidence was found for the causal effect of HF on serum urate levels. CONCLUSIONS We provide consistent evidence for the causal effect of genetically predicted serum urate level on HF, but not the reverse effect of HF. Urate-lowering therapy may be of cardiovascular benefit in the prevention of HF.