Transmembrane serine protease 2 Polymorphisms and Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection: A German Case-Control Study

Kristina Schönfelder,Carina Elsner,Birte Möhlendick,Winfried Siffert,Christian Taube,David Fistera,Karsten Schmidt,Joachim Risse,Sivagurunathan Sutharsan,Andreas Kribben,Frank Herbstreit,Ulf Dittmer,Katharina Breuckmann,Karl-Heinz Jöckel

doi:10.3389/fgene.2021.667231

Kristina Schönfelder, Carina Elsner + Show 12 more

Open Access

https://doi.org/10.3389/fgene.2021.667231

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Abstract

The transmembrane serine protease 2 (TMPRSS2) is the major host protease that enables entry of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) into host cells by spike (S) protein priming. Single nucleotide polymorphisms (SNPs) in the gene TMPRSS2 have been associated with susceptibility to and severity of H1N1 or H1N9 influenza A virus infections. Functional variants may influence SARS-CoV-2 infection risk and severity of Coronavirus disease 2019 (COVID-19) as well. Therefore, we analyzed the role of SNPs in the gene TMPRSS2 in a German case-control study. We performed genotyping of the SNPs rs2070788, rs383510, and rs12329760 in the gene TMPRSS2 in 239 SARS-CoV-2-positive and 253 SARS-CoV-2-negative patients. We analyzed the association of the SNPs with susceptibility to SARS-CoV-2 infection and severity of COVID-19. SARS-CoV-2-positive and SARS-CoV-2-negative patients did not differ regarding their demographics. The CC genotype of TMPRSS2 rs383510 was associated with a 1.73-fold increased SARS-CoV-2 infection risk, but was not correlated to severity of COVID-19. Neither TMPRSS2 rs2070788 nor rs12329760 polymorphisms were related to SARS-CoV-2 infection risk or severity of COVID-19. In a multivariable analysis (MVA), the rs383510 CC genotype remained an independent predictor for a 2-fold increased SARS-CoV-2 infection risk. In summary, our report appears to be the first showing that the intron variant rs383510 in the gene TMPRSS2 is associated with an increased risk to SARS-CoV-2 infection in a German cohort.

Highlights

The transmembrane serine protease 2 (TMPRSS2) is the major host protease that enables cell entry of several coronaviruses, e.g., HCoV-229E, SARS-CoV, and MERS, respectively (Shulla et al, 2011; Bertram et al, 2013; Shirato et al, 2013)
Based on the above described associations, we investigated the influence of the variants rs2070788, rs383510, and rs12329760 in the gene TMPRSS2 on SARS-CoV-2 infection risk and severity of COVID-19 in a German cohort
For TMPRSS2 rs12329760, we did not observe a deviation from Hardy-Weinberg equilibrium (HWE) for both SARS-CoV-2-negative and -positive patients (p = 0.66 and p = 0.50, respectively)

Summary

Introduction

The transmembrane serine protease 2 (TMPRSS2) is the major host protease that enables cell entry of several coronaviruses, e.g., HCoV-229E, SARS-CoV, and MERS, respectively (Shulla et al, 2011; Bertram et al, 2013; Shirato et al, 2013). In a recent study, Hoffmann et al (2020) demonstrated that SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as a receptor for host cell binding, and the viral spike (S) protein is cleaved into S1 and S2 by TMPRSS2 to allow fusion of the viral and cellular membranes. Single nucleotide polymorphisms (SNPs) in the gene TMPRSS2 (chromosome 21q22.3, reverse strand) have been associated with susceptibility to and severity of H1N1 or H1N9 influenza A virus infections (Cheng et al, 2015). Rs2070788, rs383510, and rs12329760, seem to be of particular interest based on preliminary work in the context of other virus infections

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