A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes.
Cardiovascular disease
Drug repurposing
Factorial Mendelian randomization
Phenome-wide association study
Uric acid
Journal
European journal of epidemiology
ISSN: 1573-7284
Titre abrégé: Eur J Epidemiol
Pays: Netherlands
ID NLM: 8508062
Informations de publication
Date de publication:
11 Jul 2024
11 Jul 2024
Historique:
received:
22
02
2024
accepted:
18
06
2024
medline:
12
7
2024
pubmed:
12
7
2024
entrez:
11
7
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38992218
doi: 10.1007/s10654-024-01138-0
pii: 10.1007/s10654-024-01138-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Cancer Research UK Career Development Fellowship
ID : C31250/A22804
Organisme : Natural Science Fund for Distinguished Young Scholars of Zhejiang Province
ID : LR22H260001
Organisme : National Nature Science Foundation of China
ID : 82204019
Organisme : MRC University Unit Transition Program grant
ID : MC_UU_00035/15
Organisme : Darwin Trust of Edinburgh
ID : Darwin Trust of Edinburgh
Informations de copyright
© 2024. The Author(s).
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