# Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?
## 9 The Renin-Angiotensin-Aldosterone System Inhibitors
It appears that the determination of variation rs4961 located within the alpha-adducin gene enables the prediction of drug response in the case of the combination of spironolactone (aldosterone antagonist) and furosemide [127]. Individuals carrying the G allele showed a better response to treatment compared with T allele carriers. In turn, variability in COVID-19 prognosis has been suggested to be associated with polymorphism of the \(ACE2\) gene and the viral \(ACE2\) receptor gene [128]. Polymorphisms within the \(ACE2\) and \(ACE\) genes (\(ACE2\) rs4240157, rs4646155, rs4830542, rs2074192 rs233575, rs2158083, and rs21068809, \(ACE\) GS790A, and I/D) were found to correlate with hypertension, and since the hypertension influences COVID-19 prognosis, the analysis of ACE2 polymorphisms in this group of patients may be of interest [128]. Moreover, [PERSON] et al. [129] found the relationship between four polymorphisms within the \(ACE2\) gene and COVID-19. According to their study, the presence of two SNPs: rs2074192 and rs1978124 appeared to exert a protective effect against COVID-19. They also showed that the DD genotype of \(ACE1\) in patients with comorbidities was associated with a greater risk of hospitalization due to COVID-19 and mortality. Similar results were obtained by [PERSON] et al. [130] who demonstrated the relation between D-allele and increased COVID-19-associated mortality. The I/D polymorphism was found to affect \(ACE2\) protein levels in lung tissue which implies that it can modulate susceptibility to SARS-CoV-2 [131]. In turn, the occurrence of SNPs rs2106809 and rs2285666 correlated with a higher risk of hospitalization and severe course of the disease. Another study revealed the positive correlation between the alternate allele (T or A) of rs2285666 and the lower infection susceptibility and case-fatality rate in the Indian population [132]. [PERSON] et al. [133] suggested that the presence of the A allele might increase the strength of the splice site thus leading to higher ACE2 serum concentration. In contrast, [PERSON] et al. [134] failed to demonstrate the impact of rs2106809 and rs2285666 on the severity of COVID-19 infection. Until now, the results of studies failed to show any clinically significant effect of RAAS inhibitors in patients with COVID-19 [135]. There is also no evidence that ACE2 is upregulated in a dose-dependent manner in the course of such treatment, therefore, it seems that RAAS inhibitors should not be discontinued, especially bearing in mind that patients with COVID-19 and hypertension have a worse COVID-19 prognosis [136]. The summary of the pharmacogenetic impacts on the treatment efficacy and adverse effects is presented in Table 1. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Drug** & **Mechanism of Action** & **Pharmacogenomic Issues** & **Effectiveness of Treatment** \\ \hline Remdesivir & Inhibition of viral replication & \(\bullet\) & 4 randomized trials: Improved recovery and a slight decrease in mortality in adults with severe COVID-19. Diminished rate of serious adverse events [22]. \\  & Inhibition of viral conversion of remdesivir [27]. & \(\bullet\) & Double-blind, randomized, placebo-controlled trial: remdesivir shortened the time to recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection [24]. \\ \hline Remdesivir & Inhibition of viral replication & \(\bullet\) & Lopinavir—rapid metabolism by the CYP3A4 enzyme—it should be co-administered with a low dose of ritonavir (CYP3A4 inhibitor) to reach optimal plasma concentrations [41; 42]. \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\  & & & \\ \end{tabular}
\end{table} 
Table 1: Impact of pharmacokinetic on the treatment efficacy and adverse effects.