Association between angiotensin-converting enzyme-2 gene polymorphism (rs2106809) with severity and outcome of COVID-19 infection.

PURPOSE: Genetic factors play important role in the severity of the COVID-19 infection since SARS-CoV-2 binds to the ACE2 receptor on the surface of host cells. ACE2 polymorphisms that may influence the expression of ACE2 can alter patients' susceptibility to COVID-19 infection or increase the severity of the disease. This study aimed to investigate the association between ACE2 rs2106809 polymorphism and the severity of the COVID-19 infection. METHODS: In this cross-sectional study, ACE2 rs2106809 polymorphism was assessed in 142 COVID-19 patients. The disease was confirmed according to clinical symptoms, imaging, and laboratory findings. The severity of the disease was graded as severe versus non-severe based on the CDC. Genomic DNA was extracted from the whole blood and PCR- RFLP was performed to genotype the ACE2-rs2106809 with specific primers and Taq1 restriction enzyme. RESULTS: G/G genotype was significantly associated with COVID-19 severity (44.4% in severe vs. 17.5% in non-severe, OR: 4.1; 95%CI: 1.8-9.5, p = 0.0007). Patients with the G/G genotype need more mechanical ventilation (p = 0.021). ACE2 expression in patients carrying the A/G genotype was higher in the severe compared to the non-severe form of the disease (2.99 ± 0.99 vs. 2.21 ± 1.1), but it was not statistically significant (p = 0.9). CONCLUSION: The G allele and G/G genotype of ACE2 rs2106809 is associated with more severe COVID-19 and adverse disease outcomes.

Polymorphisms of ACE (I/D) and ACE2 receptor gene (Rs2106809, Rs2285666) are not related to the clinical course of COVID-19: A case study.

Coronavirus disease 2019 (COVID-19) is an infectious disease, and the reason behind the currently ongoing pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme (ACE2) has been recognized as the specific receptor of the SARS-CoV-2 virus. Although the possible effect of ACE2 gene polymorphism remains unknown, human ACE2 receptor expression influences SARS-CoV-2 susceptibility and COVID-19 disease outcome. In this study, we aimed to investigate the relationship between ACE gene I/D polymorphism, ACE2 receptor gene polymorphism, and COVID-19 severity. ACE gene insertion/deletion (I/D) polymorphism and ACE2 receptor gene rs2106809 and rs2285666 polymorphisms were determined using polymerase chain reaction (PCR) and PCR-based restriction fragment length polymorphism methods, respectively, in 155 COVID-19 patients who were divided into three groups (mild, moderate, and severe) according to clinical symptoms. However, the distribution of genotype and allele frequencies of ACE gene I/D, ACE2 receptor gene rs2106809, and rs2285666 polymorphisms were not statistically significant in all groups. In conclusion, in the study population, ACE gene I/D, ACE2 receptor gene rs2106809, and rs2285666 polymorphisms were not associated with the severity of COVID-19 infection. Although ACE2 receptor gene expression may affect the susceptibility to COVID-19, there is no existing evidence that the ACE or ACE2 gene polymorphisms are directly associated with COVID-19 severity. Interindividual differences in COVID-19 severity might be related to epigenetic mechanisms of ACE2 receptor gene expression or variations in other genes suggested to play a critical role in COVID-19 pathogenesis such as pro-inflammatory cytokines and coagulation indicators.

Evaluation of a Functional Single Nucleotide Polymorphism of the SARS-CoV-2 Receptor ACE2 That Is Potentially Involved in Long COVID.

Since the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, SARS-CoV-2 has led to a global coronavirus disease 2019 (COVID-19) pandemic. A better understanding of the SARS-CoV-2 receptor ACE2 at the genetic level would help combat COVID-19, particularly for long COVID. We performed a genetic analysis of ACE2 and searched for its common potential single nucleotide polymorphisms (SNPs) with minor allele frequency >0.05 in both European and Chinese populations that would contribute to ACE2 gene expression variation. We thought that the variation of the ACE2 expression would be an important biological feature that would strongly affect COVID-19 symptoms, such as "brain fog", which is highlighted by the fact that ACE2 acts as a major cellular receptor for SARS-CoV-2 attachment and is highly expressed in brain tissues. Based on the human GTEx gene expression database, we found rs2106809 exhibited a significant correlation with the ACE2 expression among multiple brain and artery tissues. This expression correlation was replicated in an independent European brain eQTL database, Braineac. rs2106809*G also displays significantly higher frequency in Asian populations than in Europeans and displays a protective effect (p = 0.047) against COVID-19 hospitalization when comparing hospitalized COVID-19 cases with non-hospitalized COVID-19 or SARS-CoV-2 test-negative samples with European ancestry from the UK Biobank. Furthermore, we experimentally demonstrated that rs2106809*G could upregulate the transcriptional activity of ACE2. Therefore, integrative analysis and functional experiment strongly support that ACE2 SNP rs2106809 is a functional brain eQTL and its potential involvement in long COVID, which warrants further investigation.