key: cord-0770472-pit6lzsr authors: Brest, Patrick; Refae, Sadal; Mograbi, Baharia; Hofman, Paul; Milano, Gerard title: Host polymorphisms may impact SARS-CoV-2 infectivity date: 2020-08-10 journal: Trends Genet DOI: 10.1016/j.tig.2020.08.003 sha: 5332630a1bf398a7465e8482882c5723e66b22f0 doc_id: 770472 cord_uid: pit6lzsr Abstract Based on a broad public database compilation, we support the hypothesis that germinal polymorphisms may regulate the expression of the SARS-CoV-2 cellular target itself and proteases controlling the process of its shedding or, conversely, its internalization. Consequently, a genetic influence on individual susceptibility to COVID-19 infection is strongly suspected. two cell membrane proteases, ADAM17 (disintegrin and metalloproteinase domaincontaining protein 17) and TMPRSS2 (transmembrane protease serine 2) [4] . More precisely, ADAM17 acts directly on ACE2 and leads to ACE2 shedding into the extracellular cellular space while TMPRSS2 cleaves not only ACE2 but also the S protein of SARS-CoV-2, thus leading to membrane fusion and cellular uptake of the virus. Consequently, while ADAM17 and TMPRSS2 both act on ACE2, they may have opposite effects on net ACE2 shedding ( Figure 1 ). When the respective proteolytic activities of ADAM17 and TMPRSS2 result in more ACE2 shedding than internalization, it follows that this situation may constitute a natural barrier to infection. This could be due to the interaction between soluble ACE2 with the virus at a distance from sensitive tissues. Subsequently, on this basis, one can make the hypothesis that when the viral load is high the shedding barrier effect is overwhelmed, thus facilitating subsequent infection. Cao et al. [5] made a database analysis of all 1700 variants in the region of the ACE2 gene located on X chromosome. They identified 15 unique expression quantitative trait loci common variants). Interestingly, their data suggested that the 11 common variants (MAF higher than 0.05) were associated with increased expression of ACE2 in tissues, suggesting according to the authors a different sensitivity to SARS-CoV-2 infectivity. However, the functional bases for SNP influence on ACE2 expression remains to be established. reported by Cao et al [5] . It is still debatable whether these differences should be taken into consideration in epidemiological studies on COVID-19 covering ethnic associations with disease occurrence [6] . Importantly, the diseases associated with a high level of SARS-Cov-2 infection (hypertension, diabetes) were found to be related to a lower expression of ACE2, in relation to the respective allelic distribution. This relationship concurs well with the abovecommented study by Chen J. et al. pointing towards a negative correlation between ACE2 expression and COVID-19 severity [3]. It has been reported that subjects with rs383510/T and rs2070788/G genotypes of the TMPSRSS2 gene located at 21q22.3 chromosome are more prone to develop a severe form of A (H1N1) influenza and acute respiratory distress syndrome [7] . Of note, males have been shown to be more likely to develop a severe form of (H1N1) influenza and there is evidence that androgens are positive regulators of TMPRSS2 [8] . Importantly, the alleles at risk (T for rs383510 and G for rs2070788) are linked to increased gene expression (Suppl. Table) , thus logically supporting the hypothesis of a higher level of viral cell entry. It is tempting to extrapolate this SNP influence to SARS-CoV-2 infectivity. The ADAM17 locus on the 2p25.1 chromosome presents 2 clusters and 3 unique SNPs that induce strong differences in terms of allelic profiles between Asian and European populations that are associated with hypertension [9] and/or sepsis[10]. Of note, most of these SNPs are located in the promoter region of ADAM17 and are associated with either positive or negative eQTL, depending on the SNP and the tissue (Suppl . Table) . There is a strong possibility, therefore, that genetic polymorphisms influencing ADAM17 expression may also contribute to the modulation of ACE2 shedding intensity. Taken together, the above-discussed data advocate in favour of a multi-factorial genetic In summary, one can consider that, until now, genetic influence on COVID-19 interindividual susceptibility has been largely underestimated and we strongly believe that the present short Forum article may fill this gap and will pave the way for confirmatory investigations at experimental and clinical levels. TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations COVID-19: what has been learned and to be learned about the novel coronavirus disease Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A(H1N1) influenza and A(H7N9) influenza Prostate-localized and Androgen-regulated Expression of the Membrane-bound serine protease TMPRSS2 Association between ADAM17 promoter polymorphisms and ischemic stroke in a Chinese population The authors would like to thank Dr. Jocelyn Gal, Dr. Emmanuel Chamorey, Dr.George Morgan, and Dr. Christiane Brahimi-Horn for helpful comments.