Lower plasma ACE2 levels may partially mediate COVID-19 risks in overweight/obesity or low socioeconomic position

Lower plasma angiotensin-converting enzyme 2 (ACE2) levels may partially mediate COVID-19 risks in individuals with overweight/obesity or low socioeconomic position (SEP; referring to low educational attainment), according to a large-scale Mendelian randomization study conducted by researchers at the University of Hong Kong (HKU) and the Chinese University of Hong Kong (CUHK).

This study also confirmed increased COVID-19 risk among individuals with overweight/obesity, low SEP or smoking habit. However, the negative effect of smoking on COVID-19 risk was not associated with plasma ACE2 levels. [J Med Virol 2022;doi:10.1002/jmv.28205]

“It may be difficult for individuals to quit smoking or lose weight in a short time,” said Professor Kin-On Kwok of Jockey Club School of Public Health and Primary Care, CUHK, who suggested a booster dose of COVID-19 vaccine for individuals at high risk of COVID-19.

“[Therapeutic approaches] targeting ACE2 may help reduce the risk of COVID-19 among individuals who are overweight, obese, or of low SEP,” said Dr Ryan Au Yeung of School of Public Health, HKU.

The causality of risk factors on COVID-19 remains unclear. “Since ACE2 is a protein receptor for SARS-CoV-2 [entry] … it may mediate the detrimental impact of exposures on COVID-19 risk,” the researchers wrote. [J Med Virol 2022;doi:10.1002/jmv.28205]

Using summary statistics from the latest COVID-19 genome-wide association studies, the researchers analyzed independent single nucleotide polymorphisms (p<5x10^-8; r²<0.001) for exposures of interest, including lifetime smoking index (n=462,690), overweight/obesity (body mass index [BMI] and waist-to-hip ratio [WHR]; n≤694,649) and education attainment (n=3,037,499) in participants of European descent. This was followed by evaluation of the impact of COVID-19 risk factors on plasma ACE2 levels and the proportional effect of plasma ACE2 levels on COVID-19 risk factors. The study’s outcomes were COVID-19 susceptibility, hospitalization for COVID-19, and severe COVID-19.

Overall, inverse-variance weighting showed associations between increased COVID-19 risks and lifetime smoking index (susceptibility: odds ratio [OR], 1.23; 95 percent confidence interval [CI], 1.15–1.32) (hospitalization: OR, 1.61; 95 percent CI, 1.39–1.86) (severe COVID-19: OR, 1.65; 95 percent CI, 1.32–2.07), BMI (susceptibility: OR, 1.18; 95 percent CI, 1.15–1.22) (hospitalization: OR, 1.55; 95 percent CI, 1.46–1.65) (severe COVID-19: OR, 1.81; 95 percent CI, 1.65–1.99), and WHR (susceptibility: OR, 1.11; 95 percent CI, 1.06–1.16) (hospitalization: OR, 1.36; 95 percent CI, 1.22–1.51) (severe COVID-19: OR, 1.34; 95 percent CI, 1.15–1.56). In contrast, higher educational attainment was associated with lower COVID-19 risks (susceptibility: OR, 0.86; 95 percent CI, 0.83–0.90) (hospitalization: OR, 0.66; 95 percent CI, 0.60–0.72) (severe COVID-19: OR, 0.59; 95 percent CI, 0.51–0.67).

The study also showed associations between plasma ACE2 levels and all COVID-19 outcomes (susceptibility: OR, 1.11; 95 percent CI, 1.03–1.19) (hospitalization: OR, 1.21; 95 percent CI, 1.13–1.30) (severe COVID-19: OR, 1.21; 95 percent CI, 1.11–1.32). Plasma ACE2 levels were higher in individuals with higher BMI (0.14 per standard deviation [SD]; 95 percent CI, 0.07–0.20) and higher WHR (0.17 per SD; 95 percent CI, 0.08–0.26), but lower in those with higher education attainment (-0.11 per SD; 95 percent CI, -0.19 to -0.03). There was no association between plasma ACE2 levels and smoking habit.

In subsequent analysis, the proportion of association with COVID-19 outcomes mediated by plasma ACE2 was 4.3–8.2 percent for BMI, 10.7–16.8 percent for WHR, and 4.0–7.5 percent for education attainment.