Abstract
Objectives
Adiposity, smoking and lower socioeconomic position (SEP) increase COVID-19 risk whilst 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.
Methods
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 sensitivit y analyses. Mediation analyses were performed based on product of coefficient method.
Results
Higher adiposity, lifetime smoking index, and lower educational attainment were consistently associated with higher risk of COVID-19 phenotypes whilst 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 whilst ACE2 did not mediate the detrimental effect of smoking.
Conclusions
We provided genetic evidence that reducing ACE2 could partly lower COVID-19 risk amongst people who were overweight/obese or of lower SEP.
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