Identification of novel drug targets for the risk and prognosis of COVID-19

Yi-Han Gan; Ya-Nan Ou; Yu-Xiang Yang; Yue-Ting Deng; Yi Liu; Lan Tan; Jin-Tai Yu

doi:10.21037/atm-21-6612

Identification of novel drug targets for the risk and prognosis of COVID-19

Ann Transl Med. 2022 Jun;10(11):624. doi: 10.21037/atm-21-6612.

Authors

Yi-Han Gan^#¹, Ya-Nan Ou^#², Yu-Xiang Yang¹, Yue-Ting Deng¹, Yi Liu², Lan Tan², Jin-Tai Yu¹

Affiliations

¹ Department of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
² Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.

^# Contributed equally.

Abstract

Background: Since the epidemic continues, there is a pressing need to improve our understanding of coronavirus disease 2019 (COVID-19). Mendelian randomization (MR) studies provide us with a method to explore the causality between circulating proteins and COVID-19 susceptibility and severity. We aim to find new perspectives on the pathological mechanism of the disease and possible drug targets for treatment based on this study.

Methods: We conducted a phenome-wide MR study to prioritize circulating proteins causally associated with COVID-19 susceptibility, which was defined as "patients tested positive for COVID-19 vs. population controls", and severity, which was defined as "patients hospitalized with COVID-19 vs. population controls". And we repeated the analysis for different definition of COVID-19 susceptibility, severity and control groups.

Results: Association of three circulating proteins with COVID-19 susceptibility and severity were demonstrated via our study. C-C motif chemokine 4 (OR =1.887, 95% CI: 1.608-2.165, P=8.04×10^-6) and 2'-5'-oligoadenylate synthase 1 (OR =0.511, 95% CI: 0.266-0.757, P=8.51×10^-8) were found respectively positively and negatively correlated with increased COVID-19 severity. Tissue factor, contrary to previous studies, was found associated with decreased COVID-19 susceptibility (OR =0.667, 95% CI: 0.484-0.850, P=1.47×10^-5) and decreased COVID-19 severity (OR =0.459, 95% CI: 0.132-0.786, P=3.01×10^-6).

Conclusions: Genetic evidence supports C-C motif chemokine 4 as a risk factor for COVID-19 severity, and 2'-5'-oligoadenylate synthase 1 as a protective factor for COVID-19 severity. The causal association between tissue factor and COVID-19 is contrary to the previous studies, needing further analyses. Further research is warranted to assess the viability of C-C motif chemokine 4 and 2'-5'-oligoadenylate synthase 1 as well as their downstream pathways as drug targets for anti-inflammatory and anti-virus treatment in severe cases.

Keywords: Mendelian randomization (MR); coronavirus disease 2019 (COVID-19); proteomics.