Pharmacogenomics of genetic polymorphism within the genes responsible for SARS-CoV-2 susceptibility and the drug-metabolising genes used in treatment

Abstract

The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a significant challenge to international health. Pharmacogenomics aims to identify the different genetic variations that exist between individuals and populations in order to determine appropriate treatment protocols to enhance the efficacy of drugs and reduce their side-effects. This literature review provides an overview of recent studies of genetic polymorphisms in genes that mediate the SARS-CoV-2 infection mechanism (ACE1, ACE2, TMPRSS2 and CD26). In addition, genetic variations in the drug-metabolising enzyme genes of several selected drugs used in the treatment of COVID-19 are summarised. This may help construct an effective health protocol based on genetic biomarkers to optimise response to treatment. Potentially, pharmacogenomics could contribute to the development of effective high-throughput assays to improve patient evaluation, but their use will also create ethical, medical, regulatory, and legal issues, which should now be considered in the era of personalised medicine.

Keywords: COVID-19; SARS-CoV-2; drug metabolising genes; pharmacogenomics; susceptibility to SARS-CoV-2.

FIGURE 1

(a) SARS‐CoV‐2 structure showing the structural proteins, S, M, E and HE. (b) The genome organisation of SARS‐CoV‐2. (c) TMPRSS2 cleaves the S protein into two subunits [S1 subunit, and S2 subunit] during the infection process

FIGURE 2

The infection mechanism of SARS‐CoV‐2. (1) SARS‐CoV‐2 enters the target cells through the binding of viral S protein to ACE2 receptors. The viral S‐RBD binds to the ACE2 receptors, which is followed by protease cleavage of the S protein by TMPRSS2 resulting in two S subunits. (2) SARS‐CoV‐2 enters the host cells through an endosomal pathway and releases its genome. (3), (4)The viral genome is replicated, which leads to the production of ssRNA. This acts as a template to synthesise + ssRNA. (5), (6) Viral proteins are transcribed and translated in the host cell cytoplasm before the proteins are assembled into endosomal compartments. (7) The replicated genome is combined with nucleocapsid proteins and then (8) assembled into endosomal compartments. (9) Finally, the SARS‐CoV‐2 virion particles are released from the host cells and can then infect the neighbouring cells