Genetic validation of the use of tocilizumab, statins and dexamethasone in COVID-19

Schooling, C. M.; Au Yeung, S.; Kwok, M.; Zhao, J.

Background: New means of treating COVID-19 are urgently needed. Genetic validation of drugs can foreshadow trial results, and help prioritize investigations. We assessed whether common drugs, suggested as possible treatments for COVID-19 (tocilizumab, anakinra and statins) with established genetic proxies, are effective in COVID-19. We also included dexamethasone as a positive control exposure because the RECOVERY trial suggested benefit in severe COVID-19. Methods: We assessed, using Mendelian randomization, whether genetic proxies of tocilizumab, anakinra, statins and dexamethasone use affected risk of very severe (cases=536, non-cases=329391) or hospitalized (cases=3199, non-cases=897488) COVID-19 using a recent genome-wide association study. Results: Using rs2228145 (IL6R) to proxy effects of tocilizumab use, no association with very severe COVID-19 was found, but possibly an inverse association with hospitalized COVID-19 (odds ratio (OR) 0.83 per standardized effect of higher soluble interleukin-6r, 95% confidence interval 0.67 to 1.02). Using rs12916 (HMGCR) to proxy effects of statins use, an inverse association with very severe COVID-19 was found (OR 0.30 per standardized effect, 95% CI 0.10 to 0.89). Using rs6743376 and rs1542176 to proxy effects of anakinra use, no associations with COVID-19 were found. Dexamethasone, instrumented by cortisol, was possibly inversely associated with very severe COVID-19 (OR 0.20 per standardized effect 95% CI 0.04 to 1.04). Conclusion: Our study provides some genetic validation for the use of both tocilizumab and statins in COVID-19, but not anakinra, whilst being consistent with the findings from the RECOVERY trial about dexamethasone. Investigation of the underlying mechanisms might facilitate re-purposing and development of effective treatments.