key: cord-0841619-z90t7scd authors: Larsson, S. C.; Burgess, S.; Gill, D. C. title: Genetically proxied inhibition of interleukin-6 signaling: opposing associations with susceptibility to COVID-19 and pneumonia date: 2020-09-18 journal: nan DOI: 10.1101/2020.09.15.20165886 sha: 046e36524ee88560e2b246422647e4af724cdee3 doc_id: 841619 cord_uid: z90t7scd The inflammatory cytokine interleukin-6 (IL-6) is pivotal for orchestrating the immune response. Inhibitors of IL-6 signaling are being investigated as treatments for severe coronavirus disease 2019 (COVID-19). We conducted a Mendelian randomization study investigating the effect of IL-6 signaling on susceptibility to COVID-19 and pneumonia. Our results showed that genetically proxied inhibition of IL-6 signaling was associated with reduced risk of COVID-19, but also with increased risk of pneumonia. Respiratory disease is a main feature of severe COVID-19, and the potential of IL-6 signaling inhibitors to increase risk of pneumonia warrants vigilance and caution in their application to treat COVID-19. The inflammatory cytokine interleukin-6 (IL-6) is central to orchestrating the immune system. The pathophysiological process underlying severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, consists of an exaggerated host immune response and elevated circulating levels of inflammatory cytokines, including IL-6. 1 As such, immunomodulatory agents are being investigated for the treatment of COVID-19. Glucocorticoids may limit inflammation-mediated lung injury in patients with severe COVID-19, and consequently reduce progression to respiratory failure and death. The RECOVERY trial found that administration of dexamethasone resulted in lower 28-day mortality among hospitalized COVID-19 patients who were receiving either invasive mechanical ventilation or oxygen alone at randomization, but not among those who were not receiving any respiratory support. 2 Inhibition of IL-6 signaling may represent another potential immunomodulatory strategy for treating COVID-19, 3 and a recent meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease. 4 Genetic variants that proxy inhibition of IL-6 signaling may be used as instrumental variables in the Mendelian randomization paradigm to investigate corresponding drug effects. Here, we conducted a Mendelian randomization investigation to assess the potential effect of pharmacological inhibition of IL-6 signaling on susceptibility to COVID-19 and pneumonia. Inhibition of IL-6 signaling was proxied using seven single-nucleotide polymorphisms within or adjacent to the IL6R gene region that were associated with C-reactive protein (CRP; downstream molecule of IL-6 signaling) levels at the genome-wide significance threshold in 204 402 individuals of European ancestry. 5 These genetic variants also had associations with fibrinogen, IL-6 and soluble IL-6 receptor in a pattern consistent with their effect on reducing IL-6 signaling. 5 . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 18, 2020. . https://doi.org/10.1101/2020.09.15.20165886 doi: medRxiv preprint Summary-level genetic data for COVID-19 were acquired from: 1) The COVID-19 Host Genetics Initiative genome-wide association meta-analysis (round 3), 6 We performed summary data Mendelian randomization analysis using the inversevariance weighted method with multiplicative random-effects and accounting for correlations between genetic variants. Our results showed that genetically proxied inhibition of IL-6 signaling, scaled per 0.1 standard deviation lower CRP level, was associated with a reduced risk of COVID-19, but also with an increased risk of pneumonia ( Figure 1 ). Our findings provide evidence supporting that inhibition of IL-6 signaling reduces susceptibility to COVID-19. Importantly, they go further to provide genetic evidence that inhibition of IL-6 signaling may also increase susceptibility to pneumonia. While we . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 18, 2020. . https://doi.org/10.1101/2020.09.15.20165886 doi: medRxiv preprint considered a broad definition of pneumonia from any cause, our results may be of relevance to secondary lung infections that can complicate COVID-19. An adverse effect of IL-6 inhibition on risk of pneumonia risk is biologically plausible, and respiratory tract infections, including pneumonia, are a well-known complication of IL-6 signaling inhibition. 10 Respiratory disease is a main feature of severe COVID-19, and the potential of IL-6 signaling inhibitors to increase risk of pneumonia warrants vigilance and caution in their application to treat COVID-19. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 18, 2020. . https://doi.org/10.1101/2020.09.15.20165886 doi: medRxiv preprint Characterization of the inflammatory response to severe COVID-19 illness Dexamethasone in hospitalized patients with Covid-19 -Preliminary report Tocilizumab for severe COVID-19: a systematic review and meta-analysis Interleukin-6 in Covid-19: A systematic review and meta-analysis Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study Covid-19 Host Genetics Initiative. The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic FinnGen Documentation of R3 release The MR-Base platform supports systematic causal inference across the human phenome Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions The authors thank the investigators of the COVID-19 genome-wide association study, the COVID-19 Host Genetics Initiative, and FinnGen consortium for sharing summary-level data. DG is employed part-time by Novo Nordisk. The remaining authors have no conflicts of interest to disclose.