TY - JOUR
T1 - A variant in TMPRSS2 is associated with decreased disease severity in COVID-19
AU - Ravikanth, Vishnubhotla
AU - Sasikala, Mitnala
AU - Naveen, Vankadari
AU - Latha, Sabbu Sai
AU - Parsa, Kishore Venkata Laxmi
AU - Vijayasarathy, Ketavarapu
AU - Amanchy, Ramars
AU - Avanthi, Steffie
AU - Govardhan, Bale
AU - Rakesh, Kalapala
AU - Kumari, Daram Sarala
AU - Srikaran, Bojja
AU - Rao, Guduru Venkat
AU - Reddy, D. Nageshwar
N1 - Funding Information:
The authors acknowledge the funding received from Asian Healthcare Foundation. The authors acknowledge Dr. HVV Murthy, Statistician, Asian Healthcare Foundation for his help with statistical analyses. We thank the Monash University Software Platform for license and access to the concerned software. SSL acknowledges post-doctoral fellowship from Dr. Reddy's Institute of Life Sciences. KVLP and MS acknowledge the financial support from Scientific and Engineering Research Board (SERB; CRG2019002570 ).
Funding Information:
The authors acknowledge the funding received from Asian Healthcare Foundation. The authors acknowledge Dr. HVV Murthy, Statistician, Asian Healthcare Foundation for his help with statistical analyses. We thank the Monash University Software Platform for license and access to the concerned software. SSL acknowledges post-doctoral fellowship from Dr. Reddy's Institute of Life Sciences. KVLP and MS acknowledge the financial support from Scientific and Engineering Research Board (SERB; CRG2019002570). We are grateful to Dr. Kanneganti Thirumala Devi, Vice Chair of the St. Jude Children's Research Hospital, Department of Immunology, for her suggestions in revising the manuscript.
Publisher Copyright:
© 2021 Elsevier B.V.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/9
Y1 - 2021/9
N2 - Background: Mortality due to COVID-19 caused by SARS-CoV-2 infection varies among populations. Functional relevance of genetic variations in Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease 2 (TMPRSS2), two crucial host factors for viral entry, might explain some of this variation. Methods: In this comparative study in Indian subjects, we recruited 510 COVID-19 patients and retrieved DNA from 520 controls from a repository. Associations between variants in ACE2 and TMPRSS2 with disease severity were identified by whole exome sequencing (WES, n = 20) and targeted genotyping (n = 1010). Molecular dynamic simulations (MDS) were performed to explore functional relevance of the variants. Cleavage of spike glycoprotein by wild and variant TMPRSS2 was determined in HEK293T cells. Potential effects of confounders on the association between genotype and disease severity were tested (Mantel-Haenszel test). Results: WES identified deleterious variant in TMPRSS2 (rs12329760, G > A, p. V160M). The minor allele frequency (MAF) was 0·27 in controls, 0·31 in asymptomatic, 0·21 in mild-to-moderately affected and 0·19 in severely affected COVID-19 patients. Risk of severity increased with decreasing MAF: Asymptomatic: Odds ratio-0·69 (95% CI–0·52–0·93; p = 0·01); mild-to-moderate: Odds ratio-1·89 (95% CI–1·22–2.92;p = 0·004) and severe: Odds ratio-1·79 (95% CI–1·11–2.88;p = 0·01). No confounding effect of diabetes and hypertension were observed on the risk of developing severe COVID-19 disease with respect to genotype. MDS revealed decreased stability of TMPRSS2 with 160 M variant. Spike glycoprotein cleavage by TMPRSS2 reduced ~2·4-fold in cells expressing 160 M variant. Conclusion: We demonstrate association of TMPRSS2 variant rs12329760 with decreased disease severity in COVID-19 patients from India.
AB - Background: Mortality due to COVID-19 caused by SARS-CoV-2 infection varies among populations. Functional relevance of genetic variations in Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease 2 (TMPRSS2), two crucial host factors for viral entry, might explain some of this variation. Methods: In this comparative study in Indian subjects, we recruited 510 COVID-19 patients and retrieved DNA from 520 controls from a repository. Associations between variants in ACE2 and TMPRSS2 with disease severity were identified by whole exome sequencing (WES, n = 20) and targeted genotyping (n = 1010). Molecular dynamic simulations (MDS) were performed to explore functional relevance of the variants. Cleavage of spike glycoprotein by wild and variant TMPRSS2 was determined in HEK293T cells. Potential effects of confounders on the association between genotype and disease severity were tested (Mantel-Haenszel test). Results: WES identified deleterious variant in TMPRSS2 (rs12329760, G > A, p. V160M). The minor allele frequency (MAF) was 0·27 in controls, 0·31 in asymptomatic, 0·21 in mild-to-moderately affected and 0·19 in severely affected COVID-19 patients. Risk of severity increased with decreasing MAF: Asymptomatic: Odds ratio-0·69 (95% CI–0·52–0·93; p = 0·01); mild-to-moderate: Odds ratio-1·89 (95% CI–1·22–2.92;p = 0·004) and severe: Odds ratio-1·79 (95% CI–1·11–2.88;p = 0·01). No confounding effect of diabetes and hypertension were observed on the risk of developing severe COVID-19 disease with respect to genotype. MDS revealed decreased stability of TMPRSS2 with 160 M variant. Spike glycoprotein cleavage by TMPRSS2 reduced ~2·4-fold in cells expressing 160 M variant. Conclusion: We demonstrate association of TMPRSS2 variant rs12329760 with decreased disease severity in COVID-19 patients from India.
KW - ACE2
KW - COVID-19
KW - Disease severity
KW - Genotyping
KW - SARS-CoV-2
KW - TMPRSS2
UR - http://www.scopus.com/inward/record.url?scp=85107743760&partnerID=8YFLogxK
U2 - 10.1016/j.mgene.2021.100930
DO - 10.1016/j.mgene.2021.100930
M3 - Article
C2 - 34075330
AN - SCOPUS:85107743760
SN - 2214-5400
VL - 29
JO - Meta Gene
JF - Meta Gene
M1 - 100930
ER -
