In late 2019, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) outbreak was first reported in Wuhan, China that later evolved as pandemic leading to a true crisis worldwide [1]. The World Health Organization (WHO), officially named the disease ‘coronavirus disease 2019’ (COVID-19) that was manifested by a severe clinical feature, ranging from mild malaise to death by sepsis/acute respiratory distress syndrome [2]. The outbreak also occurred in Bangladesh and spread rapidly across the country since March 2020. According to WHO report, as of September 21 2021, there were 228,807,631 confirmed cases of COVID-19 with 4,697,099 deaths worldwide and 1,545,800 confirmed cases with 27,277 deaths in Bangladesh [3].

The major risk factors playing key roles in determining COVID-19 severity are age, male gender and co-existing diseases like hypertension, diabetes, obesity and coronary heart diseases [4-7]. Both the incidence and severity of COVID-19 vary among individuals and populations worldwide [8]. It is still unclear why, under similar circumstances, some individuals become infected while the others remain uninfected. In addition, it is also unexplored why the course of COVID-19 varies significantly among the infected individuals ranging from 81% mild course to 14% severe course along with 5% critical course and an in-hospital fatality ranging from 28 to 72% [6, 9]. The underlying mechanism of this variability in SARS-CoV-2 infection and COVID-19 disease severity remains to be unraveled.

Angiotensin-converting enzyme 2 (ACE2), cell surface glycoprotein, is reported to be the main entry receptor for SARS-CoV-2 (10). Infectivity and severity of SARS-CoV-2 is mostly dependent on virus entry into host cells. The initial steps of SARS-CoV-2 infection involve the specific binding of the viral S (spike) protein to the host receptor ACE2 (11, 12). ACE2 regulates the patho-physiological changes of important organs such as the lungs, kidneys, heart and gut [13]. ACE2 receptor is encoded by ACE2 gene, located on chromosome Xp22 encompassing 20 introns and 18 exons [14]. Upregulation of ACE2 expression in the airways epitheliums exposed to the virus makes individuals more susceptible to coronavirus infections [15-17].  So, the differences in ACE2 expression level may play a substantial role in defining COVID-19 susceptibility [18].

Single-nucleotide polymorphisms (SNPs) in ACE2 gene have been hypothesized to affect ACE2 expression level and the binding affinity of SARS-CoV-2, and thus influence the SARS-CoV-2 infectivity and COVID-19 severity [19-22]. ACE2 variants showed association with more severe outcomes of COVID-19 in obese smoking males in French-Canadian (FC) and British populations [23]. However, population studies on natural genetic variants of ACE2 gene are extremely limited.  Moreover, no study has been carried out on occurrence of ACE2 genetic polymorphisms among Bangladeshi population. The PI of the project has a brilliant record of research experience in studying genetic polymorphisms associated with different cancers in Bangladeshi populations [24-27]. A recent study on COVID-19 vaccination has been published in the journal Vaccines [28]. From these perspectives, we have aimed to investigate the influence of genetic polymorphisms in ACE2 receptor gene to explain the observed variability in SARS-CoV-2 infectivity and COVID-19 outcomes in Bangladeshi population.