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.
Eur J Epidemiol. 2024 Aug;39(8):869-880. doi: 10.1007/s10654-024-01138-0. Epub 2024 Jul 11.
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.
尿酸与各种疾病结局有关。然而，尿酸降低疗法是否可以被重新用于治疗痛风以外的疾病仍不清楚。我们首先进行了观察性表型全基因组关联研究（Obs-PheWAS）和多基因风险评分表型全基因组关联研究（PRS-PheWAS），以确定尿酸水平与广泛的疾病结局之间的关联。然后，进行轨迹分析以探索观察到的疾病结局的时间进展模式。最后，我们使用因子 Mendelian 随机化（MR）研究设计来研究尿酸降低药物是否可以重新用于治疗。Obs- 和 PRS-PheWAS 共确定了 41 个与尿酸水平相关的重叠表型，主要是心血管代谢疾病。轨迹分析说明了尿酸水平升高如何导致心血管代谢疾病，最终导致死亡。同时，我们发现尿酸降低药物在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：0.42，0.99，P=0.043）、脑动脉闭塞（OR=0.93，95%CI：0.87，1.00，P=0.044）和外周血管疾病（OR=0.60，95%CI：0.38，0.94，P=0.025）的风险方面发挥了保护作用。此外，尿酸降低疗法（如黄嘌呤氧化酶抑制剂）与降压治疗（如钙通道阻滞剂）联合使用具有相加作用，分别与冠状动脉粥样硬化、心力衰竭、脑动脉闭塞和外周血管疾病风险降低 6%、8%、8%、10%相关。我们的研究结果支持尿酸水平升高在心血管功能障碍进展中的作用，并确定了尿酸降低药物在心血管治疗中重新应用的潜在机会。
