School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Jockey Club School of Public Health and Primary Care, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
J Med Virol. 2023 Jan;95(1):e28205. doi: 10.1002/jmv.28205. Epub 2022 Oct 20.
Adiposity, smoking, and lower socioeconomic position (SEP) increase COVID-19 risk while the association of vitamin D, blood pressure, and glycemic traits in COVID-19 risk were less clear. Whether angiotensin-converting enzyme 2 (ACE2), the key receptor for SARS-CoV-2, mediates these associations has not been investigated. We conducted a Mendelian randomization study to assess the role of these exposures in COVID-19 and mediation by ACE2.
We extracted genetic variants strongly related to various exposures (vitamin D, blood pressure, glycemic traits, smoking, adiposity, and educational attainment [SEP proxy]), and ACE2 cis-variants from genome-wide association studies (GWAS, n ranged from 28 204 to 3 037 499) and applied them to GWAS summary statistics of ACE2 (n = 28 204) and COVID-19 (severe, hospitalized, and susceptibility, n ≤ 2 942 817). We used inverse variance weighted as the main analyses, with MR-Egger and weighted median as sensitivity analyses. Mediation analyses were performed based on product of coefficient method.
Higher adiposity, lifetime smoking index, and lower educational attainment were consistently associated with higher risk of COVID-19 phenotypes while there was no strong evidence for an association of other exposures in COVID-19 risk. ACE2 partially mediates the detrimental effects of body mass index (ranged from 4.3% to 8.2%), waist-to-hip ratio (ranged from 11.2% to 16.8%), and lower educational attainment (ranged from 4.0% to 7.5%) in COVID-19 phenotypes while ACE2 did not mediate the detrimental effect of smoking.
We provided genetic evidence that reducing ACE2 could partly lower COVID-19 risk amongst people who were overweight/obese or of lower SEP.
肥胖、吸烟和较低的社会经济地位（SEP）会增加 COVID-19 的风险，而维生素 D、血压和血糖特征与 COVID-19 风险之间的关联则不太明确。血管紧张素转换酶 2（ACE2）是 SARS-CoV-2 的关键受体，它是否介导了这些关联尚未得到研究。我们进行了一项孟德尔随机化研究，以评估这些暴露因素在 COVID-19 中的作用以及 ACE2 的中介作用。
我们从全基因组关联研究（GWAS，范围从 28204 到 3037499）中提取了与各种暴露因素（维生素 D、血压、血糖特征、吸烟、肥胖和教育程度[SEP 代理]）以及 ACE2 顺式变异密切相关的遗传变异，并将其应用于 ACE2（n=28204）和 COVID-19（严重、住院和易感性，n≤2942817）的 GWAS 汇总统计数据。我们使用逆方差加权作为主要分析方法，同时进行 MR-Egger 和加权中位数敏感性分析。基于系数乘积法进行中介分析。
较高的肥胖程度、终生吸烟指数和较低的教育程度与 COVID-19 表型的风险增加密切相关，而其他暴露因素与 COVID-19 风险之间没有强有力的关联证据。ACE2 部分介导了体重指数（范围从 4.3%到 8.2%）、腰围-臀围比（范围从 11.2%到 16.8%）和较低教育程度（范围从 4.0%到 7.5%）在 COVID-19 表型中的有害影响，而 ACE2 并未介导吸烟的有害影响。
我们提供了遗传证据，表明降低 ACE2 可以部分降低超重/肥胖或社会经济地位较低的人群 COVID-19 的风险。
