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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\u2009=\u20090.96, 95%CI: 0.93, 1.00, <jats:italic>P<\/jats:italic>\u2009=\u20090.049), congestive heart failure (OR\u2009=\u20090.64, 95%CI: 0.42, 0.99, <jats:italic>P<\/jats:italic>\u2009=\u20090.043), occlusion of cerebral arteries (OR\u2009=\u20090.93, 95%CI: 0.87, 1.00, <jats:italic>P<\/jats:italic>\u2009=\u20090.044) and peripheral vascular disease (OR\u2009=\u20090.60, 95%CI: 0.38, 0.94, <jats:italic>P<\/jats:italic>\u2009=\u20090.025). 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.<\/jats:p>","DOI":"10.1007\/s10654-024-01138-0","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T19:01:40Z","timestamp":1720724500000},"page":"869-880","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes"],"prefix":"10.1007","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9797-0753","authenticated-orcid":false,"given":"Lijuan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Mesa-Eguiagaray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James F","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Vitart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evropi","family":"Theodoratou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,11]]},"reference":[{"key":"1138_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s40885-020-00146-y","volume":"26","author":"SJ Lee","year":"2020","unstructured":"Lee SJ, Oh BK, Sung KC. 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