Yang Fangkun, Lu Yunlong, Chen Songzan, Wang Kai, Hu Teng, Cui Hanbin
Department of Cardiology, Ningbo Hospital of Zhejiang University (Ningbo First Hospital), School of Medicine, Zhejiang University, Ningbo, Zhejiang, China.
Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Nutr Metab Cardiovasc Dis. 2022 May;32(5):1266-1274. doi: 10.1016/j.numecd.2022.01.022. Epub 2022 Jan 22.
Observational studies have examined serum urate levels in relation to coronary heart disease (CHD) and myocardial infarction (MI). Whether these associations are causal remains controversial, due to confounding factors and reverse causality. We aim to investigate the causality of these associations using Mendelian randomization method.
Instrumental variables were obtained from the largest genome-wide association studies of serum urate (457,690 individuals) to date. Summary statistics were from CARDIoGRAMplusC4D consortium (60,801 CHD cases; 43,676 MI cases), FinnGen (21,012 CHD cases; 12,801 MI cases), UK Biobank (10,157 CHD cases; 7018 MI cases), and Biobank Japan (29,319 CHD cases). Inverse-variance weighted method was applied as the main results. Other statistical methods and reverse MR analysis were conducted in the supplementary analyses. Elevated genetically determined serum urate levels were associated with increased risks of CHD and MI. The association pattern remained for the datasets in FinnGen, the combined results of three independent data sources (CHD: odds ratio (OR), 1.10; 95%CI, 1.06-1.15; p = 4.2 × 10; MI: OR, 1.12; 95%CI, 1.07-1.18; p = 2.7 × 10), and East Asian population. Interestingly, sex-specific subgroup analyses revealed that these associations kept in men only, but not among women in individuals of European ancestry. No consistent evidence was found for the causal effect of CHD or MI on serum urate levels.
We provide consistent evidence for the causal effect of genetically predicted serum urate levels on CHD and MI, but not the reverse effect. Urate-lowering therapy may be of cardiovascular benefit in the prevention of CHD and MI, especially for men.
观察性研究已探讨血清尿酸水平与冠心病（CHD）及心肌梗死（MI）的关系。由于存在混杂因素和反向因果关系，这些关联是否具有因果性仍存在争议。我们旨在使用孟德尔随机化方法研究这些关联的因果性。
工具变量取自迄今为止最大规模的血清尿酸全基因组关联研究（457,690名个体）。汇总统计数据来自CARDIoGRAMplusC4D联盟（60,801例冠心病病例；43,676例心肌梗死病例）、芬兰基因研究（21,012例冠心病病例；12,801例心肌梗死病例）、英国生物银行（10,157例冠心病病例；7,018例心肌梗死病例）以及日本生物银行（29,319例冠心病病例）。主要结果采用逆方差加权法。在补充分析中进行了其他统计方法和反向孟德尔随机化分析。遗传决定的血清尿酸水平升高与冠心病和心肌梗死风险增加相关。在芬兰基因研究的数据集、三个独立数据源的合并结果（冠心病：优势比（OR），1.10；95%置信区间，1.06 - 1.15；p = 4.2×10⁻⁶；心肌梗死：OR，1.12；95%置信区间，1.07 - 1.18；p = 2.7×10⁻⁵）以及东亚人群中，这种关联模式依然存在。有趣的是，按性别进行的亚组分析显示，这些关联仅在男性中存在，而在欧洲血统个体的女性中不存在。未发现冠心病或心肌梗死对血清尿酸水平有因果效应的一致证据。
我们为遗传预测的血清尿酸水平对冠心病和心肌梗死的因果效应提供了一致证据，但未发现反向效应。降低尿酸治疗可能对预防冠心病和心肌梗死具有心血管益处，尤其是对男性。
