Exploring diseases/traits and blood proteins causally related to expression of ACE2, the putative receptor of 2019-nCov: A Mendelian Randomization analysis

Shitao Rao; Alexandria Lau; Hon-Cheong So

Interestingly, recent studies by the company BenevolentAI 44,45 employed a proprietary knowledge graph approach and found several repositioning candidates 46, 47 . Baricitinib, a JAK 1/2 inhibitor approved for RA, was suggested as a top candidate. The drug was proposed on its action on AAK1 which is a regulator of endocytosis, although how AAK1 was prioritized as target was not described in the study. Fostamatinib, which we prioritized in this study, also inhibits JAK1, JAK2 and AAK1 48 based on curations from DrugBank and was shown to be effective for RA 43 . Of note, two other JAK-STAT signaling inhibitors were recommended by Stebbing et al. 45 , while in our analysis JAK-STAT signaling is among the top 10 pathways enriched for top proteins linked to ACE2 expression. Another candidate highlighted by Richardson et al. 44 , sunitinib, was also top-listed by our MR-based analysis. We have employed a rather different algorithm based on causal inference, when compared to the approach by BenevolentAI. The concordance between different studies provides additional support to the usefulness our MR-based approach, and the drugs with converging evidence by different approaches may be more likely to be true candidates. Zinc was also a top-listed candidate in our study, and it has been reported to reduce the risk of lower respiratory tract infections in some studies, e.g. 49 , although further studies are required as the evidence is not firm.