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AbstractThere are few effective therapeutic options for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Early evidence has suggested that IL-6R blockers may confer benefit, particularly in severe coronavirus disease 2019 (Covid-19).We leveraged large-scale human genetic data to investigate whether IL6-R blockade may confer therapeutic benefit in Covid-19. A genetic instrument consisting of seven genetic variants in or close to IL6R was recently shown to be linked to altered levels of c-reactive protein (CRP), fibrinogen, circulating IL-6 and soluble IL-6R, concordant to known effects of pharmacological IL- 6R blockade. We investigated the effect of these IL6R variants on risk of hospitalization for Covid- 19 and other SARS-CoV-2-related outcomes using data from The Covid-19 Host Genetics Initiative.The IL6R variants were strongly associated with serum CRP levels in UK Biobank. Meta-analysis of scaled estimates revealed a lower risk of rheumatoid arthritis (OR 0.93 per 0.1 SD lower CRP, 95% CI, 0.90-0.96, P = 9.5 × 10−7), recapitulating this established indication for IL-6R blockers (e.g. tocilizumab and sarilumab). The IL-6R instrument was associated with lower risk of hospitalization for Covid-19 (OR 0.88 per 0.1 SD lower CRP, 95% CI, 0.78-0.99, P = 0.03). We found a consistent association when using a population-based control group (i.e. all non-cases; OR 0.91 per 0.1 SD lower CRP, 95% CI, 0.87-0.96, P = 4.9 × 10−4). Evaluation of further SARS- CoV-2-related outcomes suggested association with risk of SARS-CoV-2 infection, with no evidence of association with Covid-19 complicated by death or requiring respiratory support. We performed several sensitivity analyses to evaluate the robustness of our findings.Our results serve as genetic evidence for the potential efficacy of IL-6R blockade in Covid-19. Ongoing large-scale RCTs of IL-6R blockers will be instrumental in identifying the settings, including stage of disease, in which these agents may be effective.

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