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

Coronavirus disease 2019 (COVID-19) is more severe in obesity. A cytokine storm was observed in critically ill patients. Since adipose tissue secretes cytokines, we investigated whether cytokines mediate the effect of obesity on COVID-19 severity. Using replicated two-sample Mendelian randomization analyses, we assessed the causal effect of body mass index (BMI) on COVID-19 severity. We evaluated the BMI effect on 41 inflammatory cytokines, JAK-2, lymphocyte percentage and leptin. We tested the relationship between these immunological factors and COVID-19 severity and conducted mediation analysis.Higher BMI increased the risk of COVID-19 severity. BMI was causally associated with five inflammatory cytokines - HGF, TRAIL, IL-13, IL-6, and IL-7 - with replication confirming these associations. TNF-α and IL-8 were identified as associated with COVID-19 severity, but with no replication support. Leptin-related genetic variation was associated with COVID-19 severity and supported by replication, but JAK-2 and lymphocyte percentage provided no evidence of association. None of the immunological factors tested showed consistent statistical evidence of mediation between BMI and COVID-19 severity. Our findings support the reported causal association between BMI and COVID-19 severity. Although several cytokines elevated due to higher BMI, we observed inconsistent evidence for baseline cytokines levels increasing COVID-19 severity. Baseline levels of circulating cytokines, JAK-2, lymphocyte percentage, and leptin showed no evidence of mediating the BMI and severe COVID-19 link. Limited participants in cytokine GWASs reduce statistical power, and missing population data on cytokine responses to infection are major limitations requiring resolution to explain cytokines' mediating role between BMI and severe COVID-19.