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
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).

Références

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Auteurs

Lijuan Wang (L)

Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK.

Ines Mesa-Eguiagaray (I)

Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK.

Harry Campbell (H)

Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK.

James F Wilson (JF)

Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK.
MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.

Veronique Vitart (V)

MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.

Xue Li (X)

School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Evropi Theodoratou (E)

Centre for Global Health, Usher Institute, The University of Edinburgh, Edinburgh, UK. e.theodoratou@ed.ac.uk.
Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK. e.theodoratou@ed.ac.uk.

Classifications MeSH