Genetic gateways to COVID‐19 infection: Implications for risk, severity, and outcomes

Debnath, Monojit; Banerjee, Moinak; Berk, Michael

The dynamics, such as transmission, spatial epidemiology, and clinical course of Coronavirus Disease‐2019 (COVID‐19) have emerged as the most intriguing features and remain incompletely understood. The genetic landscape of an individual in particular, and a population in general seems to play a pivotal role in shaping the above COVID‐19 dynamics. Considering the implications of host genes in the entry and replication of SARS‐CoV‐2 and in mounting the host immune response, it appears that multiple genes might be crucially involved in the above processes. Herein, we propose three potentially important genetic gateways to COVID‐19 infection; these could explain at least in part the discrepancies of its spread, severity, and mortality. The variations within Angiotensin‐converting enzyme 2 (ACE2) gene might constitute the first genetic gateway, influencing the spatial transmission dynamics of COVID‐19. The Human Leukocyte Antigen locus, a master regulator of immunity against infection seems to be crucial in influencing susceptibility and severity of COVID‐19 and can be the second genetic gateway. The genes regulating Toll‐like receptor and complement pathways and subsequently cytokine storm induced exaggerated inflammatory pathways seem to underlie the severity of COVID‐19, and such genes might represent the third genetic gateway. Host‐pathogen interaction is a complex event and some additional genes might also contribute to the dynamics of COVID‐19. Overall, these three genetic gateways proposed here might be the critical host determinants governing the risk, severity, and outcome of COVID‐19. Genetic variations within these gateways could be key in influencing geographical discrepancies of COVID‐19.