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Multicenter Study
. 2021 Apr 19;12(4):596.
doi: 10.3390/genes12040596.

Protective Role of a TMPRSS2 Variant on Severe COVID-19 Outcome in Young Males and Elderly Women

Maria Monticelli  1 , Bruno Hay Mele  1   2 , Elisa Benetti  3 , Chiara Fallerini  3   4 , Margherita Baldassarri  3   4 , Simone Furini  3 , Elisa Frullanti  3   4 , Francesca Mari  3   4   5 , Giuseppina Andreotti  6 , Maria Vittoria Cubellis  1   6 , Alessandra Renieri  3   4   5 ; Gen-Covid Multicenter Study
Collaborators, Affiliations
Multicenter Study

Protective Role of a TMPRSS2 Variant on Severe COVID-19 Outcome in Young Males and Elderly Women

Maria Monticelli et al. Genes (Basel). .

Abstract

The protease encoded by the TMPRSS2 gene facilitates viral infections and has been implicated in the pathogenesis of SARS-CoV-2. We analyzed the TMPRSS2 sequence and correlated the protein variants with the clinical features of a cohort of 1177 patients affected by COVID-19 in Italy. Nine relatively common variants (allele frequency > 0.01) and six missense variants which may affect the protease activity according to PolyPhen-2 in HumVar-trained mode were identified. Among them, p.V197M (p.Val197Met) (rs12329760) emerges as a common variant that has a deleterious effect on the protease and a protective effect on the patients. Its role appears particularly relevant in two subgroups of patients-young males and elderly women-and among those affected by co-morbidities, where the variant frequency is higher among individuals who were mildly affected by the disease and did not need hospitalization or oxygen therapy than among those more severely affected, who required oxygen therapy, ventilation or intubation. This study provides useful information for the identification of patients at risk of developing a severe form of COVID-19, and encourages the usage of drugs affecting the expression of TMPRSS2 or inhibiting protein activity.

Keywords: COVID-19; TMPRSS2; V197M; Whole-Exome Sequencing (WES); missense mutation.

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Conflict of interest statement

The authors declare no conflict interests.

Figures

Figure 1
Figure 1
Prevalence of p.G296G or p.V197M in COVID-19 patients subdivided by different clinical outcomes. The percentages of carriers (A,B), heterozygous (C,D) and homozygous (E,F) individuals for p.G296G (A,C,E) or p.V197M (B,D,F) in each clinical category, i.e., patients who needed intubation, ventilation (CPAP/BiPAP), or oxygen therapy, patients who did not need oxygen therapy (no resp support) or were not hospitalized (nh), are reported. The 95% confidence interval around the regression line is calculated as the product of the regression standard error and the value of the 0.975-th quantile of a t distribution with 3 degrees of freedom.
Figure 2
Figure 2
TMPRSS2 structure. A linear representation of TMPRSS2 is shown in panel (A). The probably and possibly damaging mutations identified by the HumVar-trained model in wAnnovar are highlighted. The model of the region spanning from aa 187 to 526 is shown as a cartoon in panel (B). The SRCR-like domain is in deep teal cyan, peptidase domain is in marine blue, and the linker is in light pink. V197 (red), F246 (green), and S265 (yellow) belong to the SRCR-like domain.
See this image and copyright information in PMC

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