# Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?
## 9 The Renin-Angiotensin-Aldosterone System Inhibitors  
The renin-angiotensin-aldosterone system (RAAS), composed of three main compounds: renin, angiotensin II, and aldosterone is a key regulator of blood volume and systemic vascular resistance [113]. The effects of ACE2 and ACE actions are antagonistic and therefore they provide a homeostatic regulation of angiotensin (Ang) II [25; 114]. Renin participates in the transformation of angiotensin into Ang I, and in subsequent steps, Ang I is converted by ACE into Ang II (which induces vasoconstriction and hypertension via the interaction with angiotensin receptors 1R and 2R (AT1R, AT2R)), while ACE2 converts Ang II to Ang 1-7 exerting vasodilatory effects via the interaction with the Mas receptor. Eventually, Ang II promotes the release of aldosterone on the adrenal cortex, which controls blood volume, blood pressure, as well as levels of Na\({}^{+}\), K\({}^{+}\), and H\({}^{+}\)[115; 116; 117]. As mentioned above, SARS-CoV2 can enter and infect the host pulmonary cells using the angiotensin-converting enzyme ACE2 receptor expressed in the membrane of pulmonary cells, therefore it has been suggested that ACE inhibitors and angiotensin-receptor blockers could negatively or positively interfere with the viral infection process [118; 119]. Three types of drugs block the RAAS system acting at different levels: the inhibitors of the ACE (e.g., enalapril or lisinpril), the antagonists of the AT1R receptor (e.g., losartan or irbesartan), and, finally, the antagonists of aldosterone (e.g., spironolactone) [25]. The ACE inhibitors upregulate ACE2 receptors, thus they can potentially worsen the state of COVID-19 patients treated with ACE inhibitor therapy. Indeed, the upregulation of ACE2 was found to correlate with a worse COVID-19 prognosis [40]. In turn, at least in theory, angiotensin-receptor blockers could prevent virus entry at the cellular level [120]. Currently, several ongoing clinical trials are evaluating the effectiveness and safety of captopril (either alone or in combination) in patients with COVID-19 and severe pneumonia [10]. ACE inhibitors are among the most commonly used drugs in medical practice and, therefore, the pharmacogenetic aspects have been widely studied. The polymorphisms altering the disposition and response of RAAS inhibitors may affect the treatment of COVID-19 patients. For example, genetic variants of _CYP2C9_ which metabolizes losartan may condition its clinical benefits [121]. The most frequent _CYP2C9_*2 and _CYP2C9_*3 variants are characterized by diminished function. The results of studies have demonstrated that two-thirds of the white population express the wild-type genotype (_CYP2C9_*1/*1), while one-third have either the *1/*2 or *1/*3 genotypes, and less than 2.5% of individuals possess the *2/*2, *2/*3, and *3/*3 genotypes [122]. *2 and *3 variants have been reported more frequently in patients with secondary kidney diseases and higher blood pressure compared with wild-type individuals [121]. Until now, no pharmacogenetic guidelines have been published concerning the adjustment of losartan doses based on _CYP2C9_ genotyping, but such proceedingsseem beneficial since disturbed drug metabolism could cause toxicity as a result of drug accumulation [25]. Moreover, the analysis of functional polymorphisms within the \(ABCB1\) gene could help to predict the response to losartan [123] since it encodes P-glycoprotein (P-gp) mediating the transfer of xenobiotics between body compartments, and the polymorphisms with its gene modulate drug pharmacokinetics. Variations rs1045642, rs2032582, and rs1128503 are among the most important polymorphisms in \(ABCB1\)[124]. In terms of ACE inhibitors, some studies have demonstrated the association between \(ACE\) rs1799752 and variability in the effectiveness of captopril, enalapril, and lisinopril [125; 126]. Patients carrying del/del diplotype of this polymorphism (a 50-nucleotide deletion (del)) were found to show a worse clinical outcome.