Polymorphisms in ACE, ACE2, AGTR1 genes and severity of COVID-19 disease

Abstract

Background Infection by the SARS-Cov-2 virus produces in humans a disease of highly variable and unpredictable severity. The presence of frequent genetic single nucleotide polymorphisms (SNPs) in the population might lead to a greater susceptibility to infection or an exaggerated inflammatory response. SARS-CoV-2 requires the presence of the ACE2 protein to enter in the cell and ACE2 is a regulator of the renin-angiotensin system. Accordingly, we studied the associations between 8 SNPs from AGTR1, ACE2 and ACE genes and the severity of the disease produced by the SARS-Cov-2 virus. Methods 318 (aged 59.6±17.3 years, males 62.6%) COVID-19 patients were grouped based on the severity of symptoms: Outpatients (n = 104, 32.7%), hospitalized on the wards (n = 73, 23.0%), Intensive Care Unit (ICU) (n = 84, 26.4%) and deceased (n = 57, 17.9%). Comorbidity data (diabetes, hypertension, obesity, lung disease and cancer) were collected for adjustment. Genotype distribution of 8 selected SNPs among the severity groups was analyzed. Results Four SNPs in ACE2 were associated with the severity of disease. While rs2074192 andrs1978124showed a protector effectassuming an overdominant model of inheritance (G/A vs. GG-AA, OR = 0.32, 95%CI = 0.12–0.82; p = 0.016 and A/G vs. AA-GG, OR = 0.37, 95%CI: 0.14–0.96; p = 0.038, respectively); the SNPs rs2106809 and rs2285666were associated with an increased risk of being hospitalized and a severity course of the disease with recessive models of inheritance (C/C vs. T/C-T/T, OR = 11.41, 95% CI: 1.12–115.91; p = 0.012) and (A/A vs. GG-G/A, OR = 12.61, 95% CI: 1.26–125.87; p = 0.0081). As expected, an older age (OR = 1.47), male gender (OR = 1.98) and comorbidities (OR = 2.52) increased the risk of being admitted to ICU or death vs more benign outpatient course. Multivariable analysis demonstrated the role of the certain genotypes (ACE2) with the severity of COVID-19 (OR: 0.31, OR 0.37 for rs2074192 and rs1978124, and OR = 2.67, OR = 2.70 for rs2106809 and rs2285666, respectively). Hardy-Weinberg equilibrium in hospitalized group for I/D SNP in ACE was not showed (p<0.05), which might be due to the association with the disease. No association between COVID-19 disease and the different AGTR1 SNPs was evidenced on multivariable, nevertheless the A/A genotype for rs5183 showed an higher hospitalization risk in patients with comorbidities. Conclusions Different genetic variants in ACE2 were associated with a severe clinical course and death groups of patients with COVID-19. ACE2 common SNPs in the population might modulate severity of COVID-19 infection independently of other known markers like gender, age and comorbidities.

Gene Networks of Hyperglycemia, Diabetic Complications, and Human Proteins Targeted by SARS-CoV-2: What Is the Molecular Basis for Comorbidity?

“…The clinical evidence supports the role of some molecules revealed in this work in COVID-19 pathogenesis: ANGPT2 [48,49], CCL2 [50], ICAM1 [52,53], VCAM-1 [52], MIR21 [54], MMP9 [55,56], STAT3 [57], HMGB1 [58,59], SIRT1 [62,63], AGTR1 [66], APOE4 [69,70], ACE [73], CCL11 [86,87], FGF2 [89], TNF [92], PPAR-γ [95], CASP8 [115], IL8 [117], IL6 [118], PRL [119], SP1 [122], TLR4 [123], BDNF [124], CASP1 [125], CASP3 [126,127], IL18 [128], IL10 [129], TGFB1 [130], ANXA2 [131,132], HPSE [162], MAPK1 [163], CDH1 [166], FBN1 [180], GDF15 [182,183], PLAT [195][196][197], RHOA…”

“…It was shown that AGTR1 is normally downregulated by ACE2 [64] and possesses hyperglycemic activity [65]. The A/A genotype of rs5183 SNP in the AGTR1 gene was associated with higher hospitalization risk in patients with COVID-19 and comorbidities [66]. The apolipoprotein E ε4 allele (APOE4) was associated with ACE2 reduction [67] and blood glucose level [68].…”

Clinical Utility of Amplification Refractory Mutation System-Based PCR and Mutation-Specific PCR for Precise and Rapid Genotyping of Angiotensin-Converting Enzyme 1 (ACE1-rs4646996 D>I) and Angiotensin-Converting Enzyme 2 (ACE2-rs4240157T>C) Gene Variations in Coronary Artery Disease and Their Strong Association with Its Disease Susceptibility and Progression

“…Recent findings, as well as this research here within, have shown an association between the ACE D allele, diabetes, and the risk of developing cardiovascular disease [ 34 ]. However, some studies failed to discern any relationship between the ACE gene polymorphism and CAD in patients with diabetes [ 35 , 36 ]. A possible mechanism suggests that the ACE DD genotype is involved in increasing the vasoconstrictor angiotensin II as well as the degradation of the vasodilator bradykinin, which increases resistance to insulin [ 37 ].…”

“…In contrast, several investigators were not able to find an association between the ACE D allele and the risk of CAD in the populations that they had investigated [ 34 , 41 ]. It is conceivable that a gene–environment interaction may play a significant role in the predisposition to CAD [ 35 , 36 ]. The insertion/deletion (I/D) (rs4646994) polymorphism in intron 16 of the ACE gene is considered an important genetic determinant of CAD and hypertension [ 37 , 42 ].…”

Will the Use of Pharmacogenetics Improve Treatment Efficiency in COVID-19?

“…Polymorphisms within the ACE2 and ACE genes (ACE2 rs4240157, rs4646155, rs4830542, rs2074192 rs233575, rs2158083, and rs21068809, ACE G8790A, 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, Sabater Molina 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.…”