Investigating the contribution of circulating inflammatory cytokines on the link between obesity and COVID-19

Background Coronavirus disease 2019 (COVID-19), is more severe in individuals with obesity. Furthermore, a cytokine storm was observed in many critically ill patients with COVID-19. Since adipose tissue secretes cytokines, we investigated whether cytokines mediate the effect of obesity on COVID-19 severity. Methods Using two-sample Mendelian randomization analyses we assessed the causal effect of body mass index (BMI) on COVID-19 severity. We then evaluated the BMI effect on 41 inflammatory cytokines, as well as on JAK-2, lymphocyte percentage and leptin. We also tested the relationship between these immunological factors and COVID-19 severity. The estimates obtained were used in a mediation analysis to understand the immunological factors linking BMI to COVID-19 severity. Results Higher BMI increased the risk of COVID-19 severity. BMI was also causally associated with 5 of the 41 inflammatory cytokines, HGF, TRAIL, IL 13, IL6, and IL 7. We identified TNF-α and IL-8 as the only two inflammatory cytokines associated with COVID-19 severity. Leptin-related genetic variation was associated with COVID-19 severity, but JAK-2 and lymphocyte percentage were not. We found no statistical evidence of mediation of immunological factors tested on the relationship between BMI and COVID-19 severity, although our estimate was 52.8%. Conclusions We replicated the previously reported association between BMI and COVID-19 severity. We identified the inflammatory cytokines elevated due to higher BMI. Other inflammatory cytokines showed evidence for increasing COVID-19 severity. However, we were unable to find statistical evidence of baseline levels of circulating cytokines, or additional factors involved in a cytokine storm i.e. JAK-2, lymphocyte percentage, and leptin, mediating the link between BMI and severe COVID-19. Although targeting specific cytokines will be of benefit in the general population, further work on cytokine levels during early phases of COVID-19 infection is needed to provide new approaches to decrease the risk of severe COVID-19 with higher BMI.