ACE Gene Variants Rise the Risk of Severe COVID-19 in Patients With Hypertension, Dyslipidemia or Diabetes: A Spanish Pilot Study

Abstract

Coronavirus disease 19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to scale and threaten human health and public safety. It is essential to identify those risk factors that lead to a poor prognosis of the disease. A predisposing host genetic background could be one of these factors that explain the interindividual variability to COVID-19 severity. Thus, we have studied whether the rs4341 and rs4343 polymorphisms of the angiotensin converting enzyme (ACE) gene, key regulator of the renin-aldosterone-angiotensin system (RAAS), could explain the different outcomes of 128 COVID-19 patients with diverse degree of severity (33 asymptomatic or mildly symptomatic, 66 hospitalized in the general ward, and 29 admitted to the ICU). We found that G allele of rs4341 and rs4343 was associated with severe COVID-19 in hypertensive patients, independently of gender (p<0.05). G-carrier genotypes of both polymorphisms were also associated with higher mortality (p< 0.05) and higher severity of COVID-19 in dyslipidemic (p<0.05) and type 2 diabetic patients (p< 0.01). The association of G alleles with disease severity was adjusted for age, sex, BMI and number of comorbidities, suggesting that both the metabolic comorbidities and the G allele act synergistically on COVID-19 outcome. Although we did not find a direct association between serum ACE levels and COVID-19 severity, we found higher levels of ACE in the serum of patients with the GG genotype of rs4341 and rs4343 (p<0.05), what could explain the higher susceptibility to develop severe forms of the disease in patients with the GG genotype, in addition to hypertension and dyslipidemia. In conclusion, our preliminary study suggests that the G-containing genotypes of rs4341 and rs4343 confer an additional risk of adverse COVID-19 prognosis. Thus, rs4341 and rs4343 polymorphisms of ACE could be predictive markers of severity of COVID-19 in those patients with hypertension, dyslipidemia or diabetes. The knowledge of these genetic data could contribute to precision management of SARS-CoV-2 infected patients when admitted to hospital.

The association of COVID-19 severity and susceptibility and genetic risk factors: A systematic review of the literature

“… ( Gunal et al, 2021 ) ACE rs4341, rs4343 Spain 128 COVID-19 patients rs4341 and rs4343 were associated with more severe SARS-CoV-2 disease in patients with hypertension and diabetes. ( Íñiguez et al, 2021 ) ACE, ACE2 rs2106809,rs2285666 Turkey 155 COVID-19 patients No association was observed with the severity of SARS-CoV-2 infection. ( Karakaş Çelik et al, 2021 ) ACE1 Not mentioned European, Mediterranean, and the Middle East Not mentioned ACE D/I polymorphism was associated with increased COVID-19-related death.…”

“…Our review found that ACE-1 single nucleotide polymorphisms (SNP) rs4341 and rs4343 were linked to severe infection in hypertensive, dyslipidemic, and type 2 diabetic patients. rs2074192 ( ACE-2 ) and rs1799752 ( ACE-1 ) variants, and rs699 ( AGT ) SNP were also hypothesized to predict the clinical outcome of patients infected with SARS-CoV-2 ( Cafiero et al, 2021 , Íñiguez et al, 2021 ). However, we found just one study assessing the rs1799752 polymorphism of ACE-1 receptor which showed no association with ICU admission of severe COVID-19 patients ( Baştuğ et al, 2022 ).…”

Computational Network Analysis of Host Genetic Risk Variants of Severe COVID-19

“…The limited understanding of biological mechanisms and the impact of host genetic risk factors on severe COVID-19 has led researchers to identify genetic risk variants and analyze their influence on the development of severe symptoms. Our study is analogous to the molecular network analysis studies of protein interactions derived from risk variants identified from GWAS and statistical summaries conducted among different populations [3,9,29].…”

Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases

“…On the other hand, ACE2 counterbalances Ang II–AT1R effects by either stimulating an alternative pathway for Ang I degradation to produce Ang-(1–9), or by inactivating Ang II and hydrolyzing it to a heptapeptide Ang-(1–7). The latter stimulates vasodilation and activates anti-inflammatory, antifibrotic, and antithrombotic cascades via the MasR axis [ 59 , 60 ], as well as the protection of endothelial cell activity [ 57 , 58 ].…”