Angiotensin-Converting Enzyme 2 Genetic Variants Are Associated With Coronavirus Disease 2019
Year: 2021
Type: article
Abstract: To The Editor—In a recent article, Li et al [1] investigated angiotensin-converting enzyme 2 (ACE2) expression in primary epithelial cells derived from the lungs of 58 human subjects and observed no significant alteration between genders in different age groups. Furthermore, the authors highlighted minimal effects of ACE2 expression on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and host immune response against the invading virus. Although the authors concluded that other host variables and ACE2 have a role in the etiology of coronavirus disease 2019 (COVID-19), observations of interindividual variance in ACE2 expression cannot be overlooked. The expression of ACE2 in a subject has been ascribed to various reasons, one of which is the host genetic makeup. Various single-nucleotide polymorphisms (SNPs) have been reported (https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=59272); however, few of them have functional relevance. Based on these observations, we hypothesized that common SNPs in the ACE2 gene would be associated with susceptibility to SARS-CoV-2 infection or related mortality. Based on the functional relevance, a total of 7 SNPs in the ACE2 gene (rs4240157, rs4646155, rs4830542, rs2074192, rs233575, rs2158083, and rs2285666) were considered for the present investigation. The prevalence of the alternative alleles for respective SNPs were obtained from various databases such as 1000 genomes, Korean Reference Genome Database, Japanese whole-genome reference panel 8.3KJPN, Danish reference pan-genome, and medical genome project healthy control from the Spanish population. Genomic data of healthy controls from 21 countries were considered for the present analysis. The SARS-CoV-2 infection rate and death rate per million are available on the Worldometer website (https://www.worldometers.info/coronavirus/). Various data such as countries’ name, SARS-CoV-2 infection per million, and death per million in 21 countries (Bangladesh, China, Colombia, Denmark, Finland, Gambia, India, Italy, Japan, Kenya, Korea, Mexico, Nigeria, Pakistan, Peru, Sierra Leone, Spain, Sri Lanka, United Kingdom, United States of America, and Vietnam) were extracted for the present analysis (assessed on August 19, 2021) (Supplementary Table 1). The Spearman rank correlation analysis revealed a significant inverse link between alternative alleles of rs4646155, rs233575, and rs2158083 polymorphisms with SARS-CoV-2 infection (rs4646155: r=−0.617, P=.003; rs233575: r=−0.786, P<.0001; and rs2158083: r=−0.663, P=.001) and related death (rs4646155: r=−0.569, P=.008; rs233575: r=−0.725, P=.0002; and rs2158083: r=−0.553, P=.009), indicating the protective nature of alternative alleles against COVID-19 infection and mortality (Figure 1). However, no significant correlation was observed for rs4240157, rs4830542, rs2074192, and rs2285666 ACE2 polymorphisms. Correlation of alternative alleles of angiotensin-converting enzyme 2 (ACE2) polymorphisms (rs4646155, rs233575, and rs2158083) with severe acute respiratory syndrome 2 (SARS-CoV-2) infection and mortality rate. The SARS-CoV-2 infection and mortality rate per million data were obtained from the Worldometer website (https://www.worldometers.info/coronavirus/, assessed on August 19, 2021). The alternative allele frequencies for rs4646155, rs233575, and rs2158083 in healthy subjects hailed from different countries were obtained from online databases. Spearman rank coefficient analysis was performed to investigate the correlation of alternative alleles (rs4646155: T; rs233575: A; and rs2158083: T) with SARS-CoV-2 infection/million (A, C, and E) and death rate per million (B, D, and F). A P < .05 was considered as significant. It is unclear how the ACE2 alternative alleles provide protection against SARS-CoV-2 infections and mortality. Severe acute respiratory syndrome coronavirus 2 infects human cells via ACE2 receptors, whereas cells lacking ACE2 remain uninfected by the virus [2]. Thus, it can be assumed that people with lower ACE2 levels are less likely to contract SARS-CoV-2 infection than those with elevated ACE2. In addition, higher levels of soluble ACE2 have been linked with severe COVID-19 and associated death [3, 4]. Thus, subjects expressing lower levels of ACE2 are possibly protected against COVID-19 severity and related mortality. It is interesting to note that SARS-CoV-infected cells with a diminished expression of ACE2 have an imbalance in the ACE2 angiotensin II axis. Elevated angiotensin II results in greater inflammatory molecules, leading to various organ failures and clinical severity in COVID-19 [5]. Although our recent analysis indicated a significant association of alternative alleles for rs4646155, rs233575, and rs2158083 polymorphisms with SARS-CoV-2 infection and death, the possible mechanism remained unexplored, because the functional significance of these ACE2 polymorphisms is largely unknown. Given that the 3 SNPs are in the intronic region of the ACE2 gene and that variation in introns might result in altered transcription [3], it is reasonable to assume that these genetic variants contribute to COVID-19 pathogenesis. Based on the present study’s findings and earlier observations, it can be concluded that the alternative alleles of ACE2 polymorphisms (rs4646155, rs233575, and rs2158083) confer protection against SARS-CoV-2 infection and death. However, additional case-control and mechanistic studies in different populations are necessary to validate our findings. Supplementary materials are available at The Journal of Infectious Diseases online. Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author. Financial support. A.P. is supported with Senior Research Fellowship (SRF) from Indian Council of Medical Research (ICMR) New Delhi. Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Authors: Abhijit Pati, Sunali Padhi, Tapan Kumar Singh Nayak, Aditya K Panda
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3207784019