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.

ACE Gene I/D Polymorphism and Acute Pulmonary Embolism in COVID19 Pneumonia: A Potential Predisposing Role

“…In addition, demographic studies have found in the racial variance of ACE I/D genotype a potential explanation of the different prevalence and outcomes due to COVID-19. In fact, the higher frequency of the D allele seems to perfectly match with the higher mortality rates observed in the African American population, as compared to Indians and White people, and in the European populations (particularly Italian, Spanish, and French) as compared to the Asian ethnic group ( 13 , 14 ).…”

“…Indeed, several studies have also demonstrated an association between the frequency of ACE D/D polymorphism and both the prevalence and the mortality rates of COVID-19 ( 13 , 14 ).…”

Pharmacogenomics and COVID-19: clinical implications of human genome interactions with repurposed drugs

“…There are some pharmacogenetic predictors of disposition and response of RAAS inhibitors [ 120 ]. Losartan, an ACE receptor blocker and is metabolized by CYP2C9 [ 121 ].…”

Angiotensin-converting enzyme 2 and COVID-19: patients, comorbidities, and therapies

“…The single nucleotide variations were rare but population specific and deleterious, suggesting susceptibility of different populations to SARS-CoV-2. Relevant ACE2 polymorphisms under review include rs2285666, rs1978124, and rs714205 ( 324 ). Also, deleterious variants in ACE2 differed among nine populations in gnomAD, specifically Black and non-Finnish European ones: 39% versus 54%, respectively ( 325 ).…”

“…Other haplotypes comprising ACE1, ABO-locus, 9q34.2, and 3p21.31 are of interest ( 324 , 331 ). The ACE1 II genotype had a strong negative correlation with SARS-CoV-2 cases and deaths ( 332 ).…”