Serum urate and heart failure: a bidirectional Mendelian randomization study

Abstract

Aims: Observational studies indicate that serum urate level is associated with heart failure (HF). 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 HF.

Methods and results: A bidirectional Mendelian randomization (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 (1088 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. Genetically determined serum urate level was associated with HF [odds ratio (OR), 1.07; 95% confidence interval (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 HF 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.

Conclusion: 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.

Keywords: Causal association; Genetic; Heart failure; Mendelian randomization; Serum urate.