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

Aging (Albany NY). 2020 Jun 5;12(11):10087-10098. doi: 10.18632/aging.103415. Epub 2020 Jun 5.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • COVID-19
  • Cohort Studies
  • Coronavirus Infections / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Pandemics
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / genetics*
  • Polymorphism, Single Nucleotide
  • Serine Endopeptidases / genetics*
  • Serine Endopeptidases / metabolism


  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human