Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Coronavirus disease 2019 (COVID-19) via respiratory infection, was first discovered in Wuhan, China, in December 2019. Since then, the virus has become deeply entrenched in many countries and territories, and is an enormous threat to global public health and the economy. As of June 02, 2021, over 170 million cases of COVID-19 have been confirmed worldwide and 3.56 million deaths have resulted from SARS-CoV-2 infection (1). The most common clinical symptoms of COVID-19 are fever (2), dry cough, headache (3), sore throat, nausea, breathlessness, loss of taste or smell (4) while some remain asymptomatic (5, 6). Morbidity and mortality caused by COVID-19 are also closely associated with past co-existing diseases, especially cardiovascular diseases(7). Meanwhile, human genetic factors may lead to the increased transmissibility of SARS-CoV-2 and contribute to persistent progressive disease observed in a part of infected people, but these genetic factors are largely unknown (8). Firstly, four mathematical models were constructed to predict SARS-CoV-2 transmission and the effectiveness of eradication strategies (9). The effective detection rate and detection time of SARS-CoV-2 real-time reverse transcriptase–polymerase chain reaction (rRT-PCR) analysis with the sensitivity and specificity of various antibody detection methods were reviewed (10). We have further investigated that the determinants of disease severity seem to be mainly derived from host factors, such as age and lymphopenia, while genetic variation of the virus has no significant effect on the outcomes of COVID-19 (11). Furthermore, abundant studies have indicated the possible associations of ACE2 single-nucleotide polymorphisms (SNPs) and cardiovascular risks in patients with cardiovascular disease (12–14). These observations suggest how much of the variation in COVID-19 disease severity may be explained by genetic types. Hence, early warning of inflammatory infections and cardiovascular disease risks by identifying host genetic DNA polymorphisms (variants), including excessive immune responses to viruses, will greatly promote the development of new prevention and/or treatment strategies for COVID-19.
At present, the cognition of the physicochemical property of SARS-CoV-2 mostly derived from research on SARS-CoV and MERS-CoV. As is well-known, angiotensin-converting enzyme 2 (ACE2) was highly expressed in human pneumocytes, intestinal epithelial cells and endothelial cells (15, 16). Given the importance of 3D structure of proteins in protein-protein interaction (PPI) it's not surprising that any process resulting in ACE2s' 3D structure change could influence COVID-19s' cell entry. Accumulating evidence has shown that 3D structure of ACE2 might be influenced at both transcriptional and post-transcriptional levels. SNPs are able to impact on protein function, structure, stability, and abundance (17). Therefore, the fundamental role of ACE2 in virus infection created this hypothesis that different complications to SARS-CoV-2 might be due to different ACE2 SNPs (18). Since the outbreak of the COVID-19 pandemic several authors have speculated about the role of the ACE and ACE2 gene polymorphisms in disease susceptibility and severity. However, as to what extent the variable response to complications (inflammatory infections and cardiovascular disease risks) with COVID-19 is influenced by the variability of the hosts’ genetic background was almost unclear.
Using SNPs for DNA sequence comparisons are commonly used in genetic diversity and evolutionary studies, and it is especially helpful in identifying the mutated coronavirus genomes (19). Recently, ACE2 polymorphisms were mentioned in human population, and ACE2 expression could impact the susceptibility of people to cardiovascular, hypertension, dyslipidemia, diabetes and SARS-CoV-2 infection (20). For example, 8 ACE2 SNPs (rs2074192, rs233575, rs4240157, rs4646156, rs4646188, rs1978124, rs2048683, and rs879922) were related to Type 2 diabetes mellitus (T2D) (13). Furtherly, these ACE2 SNPs were correlated with diabetic related cardiovascular complications (13). The association of ACE2 (rs233575) gene polymorphisms with blood pressure was also found in adolescents (21). More discrepant outcomes to COVID-19 disease in connected with ACE2 polymorphisms (rs2074192) in obese, smoking males (21). Besides, two SNPs (K26R and S331F), observed missense variants, can reduce ACE2 receptor affinity for the spike (S) protein (22).
In this study, we speculated that genetic factors in the ACE2 gene are likely to impact the susceptibility to COVID-19 with previous coexisting disease. By establishing the SNP genotyping method and collecting literature to ACE2 polymorphisms, we chose rs2074192, rs6632677, rs4646142, rs2048683, rs4240157, five intronic SNP in ACE2, based on different genotyping, the analysis of clinical indicators is performed in COVID-19 patients. We verified the pathological degree of the COVID-19 was associated with hypertension and diabetes. Furtherly, our observations illustrated that ACE2 SNPs rs4646142 and rs6632677 may be an optimal genetic susceptibility marker for COVID-19 related cardiovascular complications. In summary, this study aims to present possible variants in the regulatory regions of ACE2, which may lead to marked inflammatory infections and cardiovascular disease clinical indicators variations in the prevalence and mortality of COVID-19. These may be further used in the genetic association study of patients with SARS-CoV-2 infection.