Epigenetic mechanisms and host factors impact ACE2 gene expression: Implications in COVID-19 susceptibility.

Background: The ACE2 protein acts as a gateway for SARS-CoV-2 in the host cell, playing an essential role in susceptibility to infection by this virus. Genetics and epigenetic mechanisms related to the ACE2 gene are associated with changes in its expression and, therefore, linked to increased susceptibility to infection. Although some variables such as sex, age, and obesity have been described as risk factors for COVID-19, the molecular causes involved in the disease susceptibility are still unknown.

Aim: To evaluate the ACE2 gene expression profiles and their association with epigenetic mechanisms and demographic or clinical variables.

Methods: In 500 adult volunteers, the mRNA expression levels of the ACE2 gene in nasopharyngeal swab samples and its methylation status in peripheral blood samples were quantified by RT-qPCR and qMSP, respectively. The existence of significant differences in the ACE2 gene expression and its determinants were evaluated in different study groups according to several demographic or clinical variables such as sex, age, body mass index (BMI), smoking, SARS-CoV-2 infection, and presence of underlying diseases such as type II diabetes mellitus (DM2), asthma and arterial hypertension (AHT).

Results: Our results show that ACE2 gene overexpression, directly involved in susceptibility to SARS-CoV-2 infection, depends on multiple host factors such as male sex, age over 30 years, smoking, the presence of obesity, and DM2. Likewise, it was determined that the ACE2 gene expression is regulated by changes in the DNA methylation patterns in its promoter region.

Conclusions: The ACE2 gene expression is highly variable, and this variability is related to habits such as smoking and demographic or clinical variables, which details the impact of environmental and host factors on our epigenome and, therefore, in susceptibility to SARS-CoV-2 infection.