SARS-CoV-2 penetrates human cells via the ACE2 (angiotensin-converting enzyme protein as a receptor. Thus, ACE2 is critical for coronavirus infection and therapy. ACE2 is abundantly expressed in the heart, pulmonary, and gastrointestinal tracts, where it plays critical regulatory roles in the cardiovascular and other biological systems. The genetic origin of ACE2 protein levels, on the other hand, is poorly understood.

For a study, researchers performed the biggest genome-wide association meta-analysis of plasma ACE2 levels in the SCALLOP Consortium, involving over 28,000 people (Systematic and Combined Analysis of Olink Proteins). The cross-sectional epidemiological correlations of circulating ACE2 were discussed. They evaluated important genetic associations with cardiometabolic phenotypes, COVID-19, and other human complex characteristics & disorders using the summary statistics–based high-definition likelihood technique. They use Mendelian randomization to predict the effect of soluble ACE2 on vascular disease outcomes and COVID-19 severity. In addition, they undertook in silico functional analysis by combining it with other forms of omics data.

They discovered ten loci, eight of which were unique, accounting for 30% of the protein’s heredity. Plasma ACE2 was found to be genetically linked to vascular illnesses, severe COVID-19, and a wide range of human complicated disorders and treatments. An X-chromosome cis–protein quantitative trait loci–based mendelian randomization analysis found that elevated ACE2 levels were associated with increased COVID-19 severity (odds ratio, 1.63 [95% CI, 1.10–2.42]; P=0.01), hospitalization (odds ratio, 1.52 [95% CI, 1.05–2.21]; P=0.03), and infection (odds ratio, 1.60 [95% CI, 1.08–2.37]; P=0.02). Tissue and cell type-specific transcriptome and epigenomic analyses found that ACE2 regulatory variations were enriched for DNA methylation sites in blood immune cells.

The genetic foundation of human plasma ACE2 was shared with cardiovascular disease, COVID-19, and other associated illnesses. The ACE2 protein’s genomic architecture has been mapped, offering a resource for future biology and clinical research on this coronavirus receptor.