A phenome-wide association and factorial Mendelian randomization study on the repurposing of uric acid-lowering drugs for cardiovascular outcomes

被引:1
作者
Wang, Lijuan [1 ]
Mesa-Eguiagaray, Ines [1 ]
Campbell, Harry [1 ]
Wilson, James F. [1 ,2 ]
Vitart, Veronique [2 ]
Li, Xue [3 ]
Theodoratou, Evropi [1 ,4 ]
机构
[1] Univ Edinburgh, Usher Inst, Ctr Global Hlth, Edinburgh, Scotland
[2] Univ Edinburgh, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Scotland
[3] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Sch Publ Hlth, Hangzhou, Zhejiang, Peoples R China
[4] Univ Edinburgh, Inst Genet & Canc, Canc Res UK Edinburgh Ctr, Edinburgh, Scotland
关键词
Uric acid; Cardiovascular disease; Phenome-wide association study; Drug repurposing; Factorial Mendelian randomization; DISEASE; HYPERURICEMIA; URATE; RISK; PREVENTION; EVENTS; GOUT;
D O I
10.1007/s10654-024-01138-0
中图分类号
R1 [预防医学、卫生学];
学科分类号
1004 ; 120402 ;
摘要
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.
引用
收藏
页码:869 / 880
页数:12
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