A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes

• Published in: European journal of epidemiology 2024-08, Vol.39 (8), p.869-880
• Main Authors: Wang, Lijuan, Mesa-Eguiagaray, Ines, Campbell, Harry, Wilson, James F, Vitart, Veronique, Li, Xue, Theodoratou, Evropi
• Format: Article
• Language: English
• Subjects: Antihypertensives; Arteries; Arteriosclerosis; Atherosclerosis; Calcium channel blockers; Calcium channels; Cardiology; Cardiovascular Diseases; Cardiovascular Diseases - genetics; Cerebral blood flow; Congestive heart failure; Coronary artery disease; Disease; Drug development; Drug Repositioning; Drugs; Epidemiology; Female; Genome-Wide Association Study; Gout; Health services; Heart failure; Humans; Infectious Diseases; Ischemia; Male; Medicine; Medicine & Public Health; Mendelian Randomization Analysis; Occlusion; Oncology; Phenomics; Phenotype; Phenotypes; Public Health; Randomization; Risk; Trajectory analysis; Uric acid; Uric Acid - blood; Vascular diseases; Xanthine oxidase
• ISSN: 0393-2990; 1573-7284; 1573-7284
• DOI: 10.1007/s10654-024-01138-0

Uric acid has been linked to various disease outcomes. However, it remains unclear whether uric acid-lowering therapy could be repurposed as a treatment for conditions other than gout. We first performed both observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) to identify associations of uric acid levels with a wide range of disease outcomes. Then, trajectory analysis was conducted to explore temporal progression patterns of the observed disease outcomes. Finally, we investigated whether uric acid-lowering drugs could be repurposed using a factorial Mendelian randomization (MR) study design. A total of 41 overlapping phenotypes associated with uric acid levels were identified by both Obs- and PRS- PheWASs, primarily cardiometabolic diseases. The trajectory analysis illustrated how elevated uric acid levels contribute to cardiometabolic diseases, and finally death. Meanwhile, we found that uric acid-lowering drugs exerted a protective role in reducing the risk of coronary atherosclerosis (OR = 0.96, 95%CI: 0.93, 1.00, P  = 0.049), congestive heart failure (OR = 0.64, 95%CI: 0.42, 0.99, P  = 0.043), occlusion of cerebral arteries (OR = 0.93, 95%CI: 0.87, 1.00, P  = 0.044) and peripheral vascular disease (OR = 0.60, 95%CI: 0.38, 0.94, P  = 0.025). Furthermore, the combination of uric acid-lowering therapy (e.g. xanthine oxidase inhibitors) with antihypertensive treatment (e.g. calcium channel blockers) exerted additive effects and was associated with a 6%, 8%, 8%, 10% reduction in risk of coronary atherosclerosis, heart failure, occlusion of cerebral arteries and peripheral vascular disease, respectively. Our findings support a role of elevated uric acid levels in advancing cardiovascular dysfunction and identify potential repurposing opportunities for uric acid-lowering drugs in cardiovascular treatment.