A common TMPRSS2 variant has a protective effect against severe COVID-19

Alessia David; Nicholas Parkinson; Thomas P Peacock; Erola Pairo-Castineira; Tarun Khanna; Aurelie Cobat; Albert Tenesa; Vanessa Sancho-Shimizu; Jean-Laurent Casanova; Laurent Abel; Wendy S. Barclay; J Kenneth Baillie; Michael J E Sternberg

doi:10.1016/j.retram.2022.103333

A common TMPRSS2 variant has a protective effect against severe COVID-19

Alessia David, Nicholas Parkinson, Thomas P Peacock, Erola Pairo-Castineira, Tarun Khanna, Aurelie Cobat, Albert Tenesa, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Laurent Abel, Wendy S. Barclay, J Kenneth Baillie, Michael J E Sternberg

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus' spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection.

METHODS: We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2 V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2 V160M to promote viral entry.

RESULTS: We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p = 0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p = 1.3 × 10 -3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells.

CONCLUSION: TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.

Original language	English
Article number	103333
Journal	Current Research in Translational Medicine
Volume	70
Issue number	2
Early online date	10 Jan 2022
DOIs	https://doi.org/10.1016/j.retram.2022.103333
Publication status	Published - May 2022

Keywords

COVID-19
COVID19 severity
SARS-CoV-2
TMPRSS2
Targeting the host to prevent

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David, A., Parkinson, N., Peacock, T. P., Pairo-Castineira, E., Khanna, T., Cobat, A., Tenesa, A., Sancho-Shimizu, V., Casanova, J-L., Abel, L., Barclay, W. S., Baillie, J. K., & Sternberg, M. J. E. (2022). A common TMPRSS2 variant has a protective effect against severe COVID-19. Current Research in Translational Medicine, 70(2), [103333]. https://doi.org/10.1016/j.retram.2022.103333

@article{1e52796a34f34b71a1f35f4b79584445,

title = "A common TMPRSS2 variant has a protective effect against severe COVID-19",

abstract = "BACKGROUND: The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus' spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection.METHODS: We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2 V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2 V160M to promote viral entry. RESULTS: We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p = 0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p = 1.3 × 10 -3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. CONCLUSION: TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.",

keywords = "COVID-19, COVID19 severity, SARS-CoV-2, TMPRSS2, Targeting the host to prevent",

author = "Alessia David and Nicholas Parkinson and Peacock, {Thomas P} and Erola Pairo-Castineira and Tarun Khanna and Aurelie Cobat and Albert Tenesa and Vanessa Sancho-Shimizu and Jean-Laurent Casanova and Laurent Abel and Barclay, {Wendy S.} and Baillie, {J Kenneth} and Sternberg, {Michael J E}",

note = "Funding Information: Dr. David reports grants from Wellcome Trust during the conduct of the study; Dr. Parkinson reports grants from Wellcome Trust during the conduct of the study; Dr. Peacock reports grants from MRC/UKRI, grants from BBSRC during the conduct of the study; Dr. Pairo-Castineira has nothing to disclose. Dr. Khanna reports grants from BBSRC during the conduct of the study; Dr. Cobat has nothing to disclose. Dr. Tenesa reports grants from BBSRC, grants from Health Data Research UK during the conduct of the study. Dr. Sancho-Shimizu reports grants from UKRI Future Leader's Fellowship during the conduct of the study; Dr. Casanova reports other from Howard Hughes Medical Institute, other from Rockefeller University, other from St. Giles Foundation, other from Fisher centre for Alzheimer's Research Foundation, other from Meyer Foundation, other from Square Foundation, other from Grandir - Fonds de solidarit{\'e} pour l'enfance, other from SCOR Corporate Foundation for Science, other from Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), other from University of Paris, other from National Institutes of Health (NIH), other from French Foundation for Medical Research (FRM), other from FRM and French National Research Agency (ANR) GENCOVID project during the conduct of the study; Dr. Abel reports other from Agence Nationale de la Recherche during the conduct of the study; Dr. Barclay reports grants from BBSRC during the conduct of the study; Dr. Baillie has nothing to disclose. Dr. Sternberg reports grants from Wellcome Trust, grants from BBSRC, during the conduct of the study. Funding Information: Wellcome Trust, BBSRC, UKRI Future Leader's Fellowship, Health Data Research UK Funding Information: The Wellcome Trust, UKRI, MRC/UKRI, Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, Fisher centre for Alzheimer's Research Foundation, Meyer Foundation, Square Foundation, Grandir Fonds de solidarit{\'e} pour l'enfance, SCOR Corporate Foundation for Science, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), University of Paris, National Institutes of Health, French Foundation for Medical Research, FRM and French National Research Agency (ANR) GENCOVID, Agence Nationale de la Recherche, Health Data Research UK and BBSRC provided funding to support the salaries of the authors but had no role in the design, data collection, analysis, interpretation of the results or writing of the report. The content of this publication is solely the responsibility of the authors. Funding Information: AD and NP were supported by the Wellcome Trust (grants 104,955/Z/14/Z, 218,242/Z/19/Z and 211,496/Z/18/Z) and TK by the BBSRC (grants BB/P011705/1 and BB/P023959/1), VSS is supported by UKRI Future Leader's Fellowship (MR/S032304/1), J-LC is supported by Howard Hughes Medical Institute , Rockefeller University, St. Giles Foundation, Fisher centre for Alzheimer's Research Foundation, Meyer Foundation, Square Foundation, Grandir - Fonds de solidarit{\'e} pour l'enfance, SCOR Corporate Foundation for Science, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), University of Paris, National Institutes of Health (R01AI088364), French Foundation for Medical Research (EQU201903007798), FRM and French National Research Agency (ANR) GENCOVID project (ANR-20-COVI-0003); LA is supported by the Agence Nationale de la Recherche (ANR-10-IAHU-01, ANR-10-LABX-62-IBEID), TPP and WSB are supported by BBSRC grants BB/R013071/1 and BBSRC and the G2P-UK National Virology consortium (funded by MRC/UKRI, grant ref: MR/W005611/1), AT was supported by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10,002,070 and BBS/E/D/30,002,275) and Health Data Research UK (references HDR-9004 and HDR-9003). Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = may,

doi = "10.1016/j.retram.2022.103333",

language = "English",

volume = "70",

journal = "Current Research in Translational Medicine",

issn = "2452-3186",

publisher = "Elsevier B.V.",

number = "2",

}

TY - JOUR

T1 - A common TMPRSS2 variant has a protective effect against severe COVID-19

AU - David, Alessia

AU - Parkinson, Nicholas

AU - Peacock, Thomas P

AU - Pairo-Castineira, Erola

AU - Khanna, Tarun

AU - Cobat, Aurelie

AU - Tenesa, Albert

AU - Sancho-Shimizu, Vanessa

AU - Casanova, Jean-Laurent

AU - Abel, Laurent

AU - Barclay, Wendy S.

AU - Baillie, J Kenneth

AU - Sternberg, Michael J E

N1 - Funding Information: Dr. David reports grants from Wellcome Trust during the conduct of the study; Dr. Parkinson reports grants from Wellcome Trust during the conduct of the study; Dr. Peacock reports grants from MRC/UKRI, grants from BBSRC during the conduct of the study; Dr. Pairo-Castineira has nothing to disclose. Dr. Khanna reports grants from BBSRC during the conduct of the study; Dr. Cobat has nothing to disclose. Dr. Tenesa reports grants from BBSRC, grants from Health Data Research UK during the conduct of the study. Dr. Sancho-Shimizu reports grants from UKRI Future Leader's Fellowship during the conduct of the study; Dr. Casanova reports other from Howard Hughes Medical Institute, other from Rockefeller University, other from St. Giles Foundation, other from Fisher centre for Alzheimer's Research Foundation, other from Meyer Foundation, other from Square Foundation, other from Grandir - Fonds de solidarité pour l'enfance, other from SCOR Corporate Foundation for Science, other from Institut National de la Santé et de la Recherche Médicale (INSERM), other from University of Paris, other from National Institutes of Health (NIH), other from French Foundation for Medical Research (FRM), other from FRM and French National Research Agency (ANR) GENCOVID project during the conduct of the study; Dr. Abel reports other from Agence Nationale de la Recherche during the conduct of the study; Dr. Barclay reports grants from BBSRC during the conduct of the study; Dr. Baillie has nothing to disclose. Dr. Sternberg reports grants from Wellcome Trust, grants from BBSRC, during the conduct of the study. Funding Information: Wellcome Trust, BBSRC, UKRI Future Leader's Fellowship, Health Data Research UK Funding Information: The Wellcome Trust, UKRI, MRC/UKRI, Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, Fisher centre for Alzheimer's Research Foundation, Meyer Foundation, Square Foundation, Grandir Fonds de solidarité pour l'enfance, SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris, National Institutes of Health, French Foundation for Medical Research, FRM and French National Research Agency (ANR) GENCOVID, Agence Nationale de la Recherche, Health Data Research UK and BBSRC provided funding to support the salaries of the authors but had no role in the design, data collection, analysis, interpretation of the results or writing of the report. The content of this publication is solely the responsibility of the authors. Funding Information: AD and NP were supported by the Wellcome Trust (grants 104,955/Z/14/Z, 218,242/Z/19/Z and 211,496/Z/18/Z) and TK by the BBSRC (grants BB/P011705/1 and BB/P023959/1), VSS is supported by UKRI Future Leader's Fellowship (MR/S032304/1), J-LC is supported by Howard Hughes Medical Institute , Rockefeller University, St. Giles Foundation, Fisher centre for Alzheimer's Research Foundation, Meyer Foundation, Square Foundation, Grandir - Fonds de solidarité pour l'enfance, SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris, National Institutes of Health (R01AI088364), French Foundation for Medical Research (EQU201903007798), FRM and French National Research Agency (ANR) GENCOVID project (ANR-20-COVI-0003); LA is supported by the Agence Nationale de la Recherche (ANR-10-IAHU-01, ANR-10-LABX-62-IBEID), TPP and WSB are supported by BBSRC grants BB/R013071/1 and BBSRC and the G2P-UK National Virology consortium (funded by MRC/UKRI, grant ref: MR/W005611/1), AT was supported by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10,002,070 and BBS/E/D/30,002,275) and Health Data Research UK (references HDR-9004 and HDR-9003). Publisher Copyright: © 2022 The Authors

PY - 2022/5

Y1 - 2022/5

N2 - BACKGROUND: The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus' spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection.METHODS: We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2 V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2 V160M to promote viral entry. RESULTS: We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p = 0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p = 1.3 × 10 -3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. CONCLUSION: TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.

AB - BACKGROUND: The human protein transmembrane protease serine type 2 (TMPRSS2) plays a key role in SARS-CoV-2 infection, as it is required to activate the virus' spike protein, facilitating entry into target cells. We hypothesized that naturally-occurring TMPRSS2 human genetic variants affecting the structure and function of the TMPRSS2 protein may modulate the severity of SARS-CoV-2 infection.METHODS: We focused on the only common TMPRSS2 non-synonymous variant predicted to be damaging (rs12329760 C>T, p.V160M), which has a minor allele frequency ranging from 0.14 in Ashkenazi Jewish to 0.38 in East Asians. We analysed the association between the rs12329760 and COVID-19 severity in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units recruited as part of the GenOMICC (Genetics Of Mortality In Critical Care) study. Logistic regression analyses were adjusted for sex, age and deprivation index. For in vitro studies, HEK293 cells were co-transfected with ACE2 and either TMPRSS2 wild type or mutant (TMPRSS2 V160M). A SARS-CoV-2 pseudovirus entry assay was used to investigate the ability of TMPRSS2 V160M to promote viral entry. RESULTS: We show that the T allele of rs12329760 is associated with a reduced likelihood of developing severe COVID-19 (OR 0.87, 95%CI:0.79-0.97, p = 0.01). This association was stronger in homozygous individuals when compared to the general population (OR 0.65, 95%CI:0.50-0.84, p = 1.3 × 10 -3). We demonstrate in vitro that this variant, which causes the amino acid substitution valine to methionine, affects the catalytic activity of TMPRSS2 and is less able to support SARS-CoV-2 spike-mediated entry into cells. CONCLUSION: TMPRSS2 rs12329760 is a common variant associated with a significantly decreased risk of severe COVID-19. Further studies are needed to assess the expression of TMPRSS2 across different age groups. Moreover, our results identify TMPRSS2 as a promising drug target, with a potential role for camostat mesilate, a drug approved for the treatment of chronic pancreatitis and postoperative reflux esophagitis, in the treatment of COVID-19. Clinical trials are needed to confirm this.

KW - COVID-19

KW - COVID19 severity

KW - SARS-CoV-2

KW - TMPRSS2

KW - Targeting the host to prevent

U2 - 10.1016/j.retram.2022.103333

DO - 10.1016/j.retram.2022.103333

M3 - Article

C2 - 35104687

VL - 70

JO - Current Research in Translational Medicine

JF - Current Research in Translational Medicine

SN - 2452-3186

IS - 2

M1 - 103333

ER -

A common TMPRSS2 variant has a protective effect against severe COVID-19

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Keywords

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