Abstract
There 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.
Competing Interest Statement
J.B. has served as a consultant to the Bill and Melinda Gates Foundation Strategic Investment Fund. C.M.L. has collaborated with Novo Nordisk and Bayer in research, and in accordance with a university agreement, did not accept any personal payment. M.V.H. has collaborated with Boehringer Ingelheim in research, and in accordance with the policy of the Clinical Trial Service Unit and Epidemiological Studies Unit (University of Oxford), did not accept any personal payment.
Funding Statement
J.B. is supported by funding from the Rhodes Trust, Clarendon Fund and the Medical Sciences Doctoral Training Centre, University of Oxford. C.M.L. is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds, and the National Institute for Health Research Oxford Biomedical Research Centre; M.V.H. works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre.
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Data Availability
All data included in this study are publicly available. All sources are stated in the manuscript.