Genetic Hypothesis and Pharmacogenetics Side of Renin-Angiotensin-System in COVID-19

Abstract

The importance of host genetics and demography in coronavirus disease 2019 (COVID-19) is a crucial aspect of infection, prognosis and associated case fatality rate. Individual genetic landscapes can contribute to understand Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) burden and can give information on how to fight virus spreading and the associated severe acute respiratory distress syndrome (ARDS). The spread and pathogenicity of the virus have become pandemic on specific geographic areas and ethnicities. Interestingly, SARS-CoV-2 firstly emerged in East Asia and next in Europe, where it has caused higher morbidity and mortality. This is a peculiar feature of SARS-CoV-2, different from past global viral infections (i.e., SARS-1 or MERS); it shares with the previous pandemics strong age- and sex-dependent gaps in the disease outcome. The observation that the severest COVID-19 patients are more likely to have a history of hypertension, diabetes and/or cardiovascular disease and receive Renin-Angiotensin-System (RAS) inhibitor treatment raised the hypothesis that RAS-unbalancing may have a crucial role. Accordingly, we recently published a genetic hypothesis on the role of RAS-pathway genes (ACE1, rs4646994, rs1799752, rs4340, rs13447447; and ACE2, rs2285666, rs1978124, rs714205) and ABO-locus (rs495828, rs8176746) in COVID-19 prognosis, suspecting inherited genetic predispositions to be predictive of COVID-19 severity. In addition, recently, Genome-Wide Association Studies (GWAS) found COVID-19-association signals at locus 3p21.31 (rs11385942) comprising the solute carrier SLC6A20 (Na+ and Cl- coupled transporter family) and at locus 9q34.2 (rs657152) coincident with ABO-blood group (rs8176747, rs41302905, rs8176719), and interestingly, both loci are associated to RAS-pathway. Finally, ACE1 and ACE2 haplotypes seem to provide plausible explanations for why SARS-CoV-2 have affected more heavily some ethnic groups, namely people with European ancestry, than Asians.

Keywords: ACE1; ACE2; COVID-19; RAS-pathway; SARS-CoV-2; gender-gap; prognostic markers.

Figure 1

Schematic representation of the renin-angiotensin-system (RAS) pathway showing the main bioactive peptides and key receptors. ACE1, angiotensin-converting enzyme 1; ACE2, angiotensin-converting enzyme 2; Ang, angiotensin; AT1R, Ang-II type 1 receptor; AT2R, Ang-II type 2 receptor; ARBs, angiotensin receptor blockers; MAS, Mas receptor; AT4R, angiotensin receptor type 4; MrgD, MAS-related G protein-coupled receptor member D; APA, aminopeptidase A; APN, aminopeptidase N; DC, decarboxylase.

Figure 2

Hypothesized mechanisms of different genetic haplotypes in ACE1 and ACE2 genes in the RAS pathway. Upper panel, the ACE2 downregulation due to virus entry is exacerbated by “loss of function” ACE2 8790 G/G genotype (homozygous G/G females and hemizygous G/- males). The coexistence of ACE1 upregulation due to “gain of function” D/D genotype leads on unrestrained RAS deregulation and ARDS establishment. Lower panel, the ACE2 downregulation due to virus entry is weakened by “gain of function” ACE2 8790 A/A genotype (homozygous A/A females and hemizygous A/- males). The coexistence of ACE1 downregulation due to “loss of function” I/I genotype counteracts RAS unbalancing avoiding ARDS establishment.