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

The copyright holder for this preprint . https://doi.org/10.1101/2020.03. 30.20047878 doi: medRxiv preprint with different disease manifestations are urgently needed. Among the analyzed hypotheses, the most interesting signals refer to sex-related differences in TMPRSS2 expression and in genetic variation in TMPRSS2. In particular, we identified an exonic variant (p.Val160Met) and 2 distinct haplotypes showing profound frequency differences between East Asians and Italians. The rare alleles of these haplotypes, all predicted to induce higher levels of TMPRSS2, are more frequent in the Italian than in the East Asian population; in one case, the haplotype could be regulated through androgens (possibly explaining the sex bias in COVID-19 severity?), in the other case, a SNP belonging to the haplotype has been associated with increased susceptibility to influenza, possibly related to a higher susceptibility in Italians and Europeans. Our data, beside suggesting possible explanations for the unusually high, relative to known data, lethality rates among Italians, provide reference frequencies in the general Italian population for candidate variants that can be compared to genetic data from patients infected by SARS-CoV-2 with different disease manifestations, as soon as they will be available on large numbers of patients. These studies will hopefully help to identify useful prognostic markers to stratify patients and provide the best care to high-risk individuals.