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

Concerning common exonic variants, the only striking difference, as also noticed by Cao and colleagues, 20 was observed for the single nucleotide polymorphism (SNP) rs2285666 (also called G8790A), with the frequency of the rare A allele being 0.2 in Italians and Europeans, and 0.55 in East Asians (P=2.2*10-16 for difference in Italians vs East Asians; Table 1B ). This variant was extensively studied as a potential risk factor for hypertension, type 2 diabetes, and coronary artery disease, 21,22 hence possibly constituting a predisposing factor also for the comorbidities observed in COVID-19 patients. A single paper reports the association of the three rs2285666 genotypes with ACE2 protein level measured in serum by ELISA, with the A/A genotype having an expression level almost 50% higher than the G/G genotype. 23 Given the position of the variant, at nucleotide +4 in the donor splice site of intron 3 manifestations. Of note, no eQTL for ACE2 in the lung has been described so far in the GTEx database, and investigations on this topic are recommended.