ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy

Abstract

As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has one of the highest numbers of SARS-CoV-2-related deaths and one of the highest mortality rates. Worldwide, a more severe course of COVID-19 is associated with older age, comorbidities, and male sex. Hence, we searched for possible genetic components of COVID-19 severity among Italians by looking at expression levels and variants in ACE2 and TMPRSS2 genes, crucial for viral infection.Exome and SNP-array data from a large Italian cohort were used to compare the rare-variants burden and polymorphisms frequency with Europeans and East Asians. Moreover, we looked into gene expression databases to check for sex-unbalanced expression.While we found no significant evidence that ACE2 is associated with disease severity/sex bias, TMPRSS2 levels and genetic variants proved to be possible candidate disease modulators, prompting for rapid experimental validations on large patient cohorts.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; genetic variants.

Figure 1

ACE2 expression levels. All panels show ACE2 mRNA expression levels in human normal lung samples stratified according to sex (or on sex and age). On left panels, data were retrieved for a total of 578 RNAseq experiments from the GTex repository. Expression levels are reported as transcripts per kilobase million (TPM). On the right, data were collected from two different datasets (GSE66499 and GSE19804) from the GEO database. Expression levels are reported as normalized signal intensities. P values were calculated by using either the Kruskal-Wallis or the student t test, using the R software (https://www.r-project.org/).

Figure 2

TMPRSS2 expression levels and eQTLs. (A) Both panels show TMPRSS2 mRNA expression levels in human normal lung samples stratified according to sex. On the left, data were retrieved for a total of 578 RNAseq experiments from the GTex repository. Expression levels are reported as transcripts per kilobase million (TPM). On the right, data were collected for a total of 170 microarray experiments from the GEO database. Expression levels are reported as normalized signal intensities. P values were calculated by using either the Kruskal-Wallis or the student t test. (B) Screenshot from the UCSC Genome browser (http://genome.ucsc.edu/; GRCh37/hg19) highlighting the TMPRSS2 region (coordinates chr21: 42,835,000-42,905,000). The panel shows the following tracks: i) the ruler with the scale at the genomic level; ii) chromosome 21 nucleotide numbering; iii) the UCSC RefSeq track; iv) enhancers (grey and red bars) from GeneHancer database; v) interactions (curved lines) connecting GeneHancer regulatory elements and genes: all curved lines converge towards the androgen-responsive enhancer for the TMPRSS2 gene described by Clinckemalie and colleagues [29].