ENaC gene variants and their involvement in Covid‑19 severity

Abstract

Epidemiological studies report the association of diverse cardiovascular conditions with coronavirus disease 2019 (COVID-19), but the causality has remained to be established. Specific genetic factors and the extent to which they can explain variation in susceptibility or severity are largely elusive. The present study aimed to evaluate the link between 32 cardio-metabolic traits and COVID-19. A total of 60 participants were enrolled, who were categorized into the following 4 groups: A control group with no COVID-19 or any other underlying pathologies, a group of patients with a certain form of dyslipidemia and predisposition to atherosclerotic disease, a COVID-19 group with mild or no symptoms and a COVID-19 group with severe symptomatology hospitalized at the Intensive Care Unit of Sotiria Hospital (Athens, Greece). Demographic, clinical and laboratory data were recorded and genetic material was isolated, followed by simultaneous analysis of the genes related to dyslipidemia using a custom-made next-generation sequencing panel. In the COVID-19 group with mild or absent symptoms, the variant c.112C>T:p.P38S was detected in the sodium channel epithelial 1 subunit α (SCNN1A) gene, with a major allele frequency (Maf) of <0.01. In the COVID-19 group with severe symptoms, the variant c.786G>A:p.T262T was detected in the SCNN1B gene, which encodes for the β-subunit of the epithelial sodium channel ENaC, with a Maf <0.01. None of the two rare variants were detected in the control or dyslipidemia groups. In conclusion, the current study suggests that ENaC variants are likely associated with genetic susceptibility to COVID-19, supporting the rationale for the risk and protective genetic factors for the morbidity and mortality of COVID-19.

Keywords: ENaC; SARS-Cov2; atherosclerosis; dyslipidemia; genetics.

Figure 1

Logo representation of multiple sequence alignment of the sodium channel epithelial 1 subunit β protein and the conserved residue T262.

Figure 2

Left panel: The three-dimensional structure of epithelial sodium channel ENaC in cartoon representation assembled by the three subunits α (purple), β (blue) and γ (yellow), consisting of six helices that span the cell membrane and a large extracellular domain. Right panel: Threonine residue T262 of sodium channel epithelial 1 subunit β exposed on the surface.

Figure 3

GeneMANIA genetic network for the SCNN1A-SCNN1B genes. SCNN1A, sodium channel epithelial 1 subunit α (related to the genes SCNN1G, SFTPB, ACE2, KDM3, TMPRSS2, ASIC1, ASIC2, ASIC3, SGK1, SGK2, C8ORF44, WWP1, NEDD4, NEDD4L, TSC22D3, WNK2, WNK1, WNK4, WNK3, PSAP and PSAPL1).

Figure 4

Potential role of ENaC in the pathogenesis of Coronavirus disease 2019. ENAC, epithelial sodium channel; S1, substrate 1; S protein, spike protein; α/β/γ, alpha/beta/gamma subunits.