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

Rosanna Asselta; Elvezia Maria Paraboschi; Alberto Mantovani; Stefano Duga

For most X-chromosome genes, the double allelic dosage in women is balanced by the epigenetic silencing of one of the X chromosomes in early development. 15 However, the X-chromosome inactivation (XCI) is incomplete in humans and up to one third of genes are expressed from both alleles, with the degree of XCI escape varying between genes and individuals. 16 ACE2 is one of the genes escaping X inactivation, but it belongs to a subgroup of X-chromosome genes escaping XCI showing an uncharacteristically heterogeneous pattern of male-female expression, with higher expression in men in several tissues. 17 Specifically concerning the lung, a recent analysis on published expression data, reported a substantial similar level of ACE2 transcript in men and women, 18 however, another study, using single-cell sequencing, found a higher expression of ACE2 in Asian men. 19 Supplementary Figure 1 reports data on ACE2 mRNA expression levels in the lung as retrieved from the largest datasets available in the literature; no substantial differences were found between males and females, nor between younger and older women, thus confirming what already observed by Cai and colleagues. 18 Another possible sex-related effect might be due to the fact that males are hemizygous for the gene, therefore, in the presence of an ACE2 allelic variant increasing disease susceptibility or severity, men will have all cells expressing the risk variant. Based on this hypothesis, we looked into the genetic variation in ACE2. A recent manuscript explored this same topic in different populations using data from public databases. 20 However, a specific analysis of the Italian population is Iacking.