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.

尿酸与多种疾病结果有关。然而，目前尚不清楚降尿酸疗法是否可以重新用于治疗痛风以外的疾病。我们首先进行了观察性表组范围关联研究 (Obs-PheWAS) 和多基因风险评分 PheWAS (PRS-PheWAS)，以确定尿酸水平与多种疾病结果的关联。然后，进行轨迹分析以探索观察到的疾病结果的时间进展模式。最后，我们研究了是否可以使用阶乘孟德尔随机化 (MR) 研究设计来重新利用降尿酸药物。 Obs- 和 PRS- PheWAS 共鉴定出 41 种与尿酸水平相关的重叠表型，主要是心脏代谢疾病。轨迹分析说明了尿酸水平升高如何导致心脏代谢疾病，并最终导致死亡。同时，我们发现降尿酸药物对降低冠状动脉粥样硬化（OR = 0.96，95%CI：0.93，1.00， P = 0.049）、充血性心力衰竭（OR = 0.64，95%CI）的风险具有保护作用。 ：0.42，0.99， P = 0.043），脑动脉闭塞（OR = 0.93，95％CI：0.87，1.00， P = 0.044）和周围血管疾病（OR = 0.60，95％CI：0.38，0.94， P = 0.025）。此外，降尿酸治疗（如黄嘌呤氧化酶抑制剂）与抗高血压治疗（如钙通道阻滞剂）相结合可产生相加效应，可使冠状动脉粥样硬化风险降低 6%、8%、8%、10% 、心力衰竭、脑动脉闭塞和周围血管疾病。 我们的研究结果支持尿酸水平升高在促进心血管功能障碍中的作用，并确定了降尿酸药物在心血管治疗中的潜在重新利用机会。