Abstract
Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10 -4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.
Original language | English (US) |
---|---|
Article number | 0958 |
Journal | Royal Society Open Science |
Volume | 7 |
Issue number | 11 |
DOIs | |
State | Published - Nov 1 2020 |
All Science Journal Classification (ASJC) codes
- General
Keywords
- COVID-19
- Mendelian randomization
- angiotensin-converting enzyme inhibitors
- genetic epidemiology
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In: Royal Society Open Science, Vol. 7, No. 11, 0958, 01.11.2020.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels
T2 - A Mendelian randomization study: ACE inhibition and ACE2 expression
AU - Gill, Dipender
AU - Arvanitis, Marios
AU - Carter, Paul
AU - Hernández Cordero, Ana I.
AU - Jo, Brian
AU - Karhunen, Ville
AU - Larsson, Susanna C.
AU - Li, Xuan
AU - Lockhart, Sam M.
AU - Mason, Amy
AU - Pashos, Evanthia
AU - Saha, Ashis
AU - Tan, Vanessa Y.
AU - Zuber, Verena
AU - Bossé, Yohan
AU - Fahle, Sarah
AU - Hao, Ke
AU - Jiang, Tao
AU - Joubert, Philippe
AU - Lunt, Alan C.
AU - Ouwehand, Willem Hendrik
AU - Roberts, David J.
AU - Timens, Wim
AU - Van Den Berge, Maarten
AU - Watkins, Nicholas A.
AU - Battle, Alexis
AU - Butterworth, Adam S.
AU - Danesh, John
AU - Di Angelantonio, Emanuele
AU - Engelhardt, Barbara E.
AU - Peters, James E.
AU - Sin, Don D.
AU - Burgess, Stephen
N1 - Funding Information: Ethics. The data used in this work are obtained from published studies that obtained relevant participant consent and ethical approval. Data accessibility. All variants used as instruments and their genetic association estimates were selected from publicly available data sources and are provided in electronic supplementary material, Tables S1–S8. GWAS summary data for all the outcomes considered in this study are publicly available at http://dx.doi.org/10.6084/m9.figshare. 12102681 (GTEx), http://dx.doi.org/10.6084/m9.figshare.12102711 (Lung eQTL Consortium), and http://dx.doi. org/10.6084/m9.figshare.12102777 (INTERVAL). The results from the analyses performed in this work are presented in the main manuscript or its supplementary files. Authors’ contributions. D.G. and S.B. designed the project. X.L., N.A.W., W.H.O., D.J.R., S.F., T.J., W.T., W.v.d.B., Y.B., P.J., K.H., A.B., D.D.S., J.E.P., A.S.B., B.E.E. and J.D. provided the data. S.B., D.G., J.E.P. and S.C.L. analysed the data. D.G., S.B., V.Z. and J.E.P. drafted the manuscript. All authors interpreted the results and critically revised the manuscript. Competing interests. D.G. is a part-time employee of Novo Nordisk. A.S.B. reports grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, Pfizer and Sanofi and personal fees from Novartis. B.E.E. is on the scientific advisory boards of Freenome and Celsius Therapeutics and is a full-time employee at Genomics plc while on a leave of absence from Princeton University. J.E.P. has received travel and accommodation expenses and hospitality from Olink to speak at Olink-sponsored academic meetings. E.P. is a full-time employee of Pfizer. J.D. reports grants, personal fees and non-financial support from Merck Sharp & Dohme (MSD), grants, personal fees and non-financial support from Novartis, grants from Pfizer and grants from AstraZeneca outside the submitted work. J.D. sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science ’Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the AstraZeneca Genomics Advisory Board (since 2018). All other authors have no conflicts of interest to declare. Funding. D.G. is supported by the Wellcome Trust 4i Programme (203928/Z/16/Z) and British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London. S.B. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (award no. 204623/Z/16/Z). The academic coordinating centre for INTERVAL at Cambridge University was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/ L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust), and Health Data Research UK. S.F. is funded by the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). J.D. holds a British Heart Foundation Professorship and a National Institute for Health Research Senior Investigator Award. S.C.L. is funded by the Swedish Heart-Lung Foundation, the Swedish Research Council and the Swedish Research Council for Health, Working Life and Welfare. V.K. is funded by a European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant no. 721567. V.Y.T. is supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A19169). S.M.L. is supported by an Academic Clinical Fellowship from the NIHR. Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. J.E.P. is supported by a UKRI Innovation Fellowship at Health Data Research UK (MR/S004068/1). T.J. is funded by the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. A.M.M. is funded by the European Council Innovative Medicines Initiative (BigData@Heart). This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and the Wellcome Trust. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). Donors were enrolled at Biospecimen Source Sites funded by Leidos Biomedical, Inc. (Leidos) subcontracts to the National Disease Research Interchange (10XS170) and Roswell Park Cancer Institute (10XS171). The Laboratory, Data Analysis and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos subcontract to Van Andel Institute (10ST1035). Additional data repository and project management provided by Leidos (HHSN261200800001E). Acknowledgements. We would like to thank those children and family members who allowed us time to work on this manuscript despite disruptions to schooling and daily routine. Participants in the INTERVAL BioResource were Funding Information: recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported fieldwork and other elements of the trial. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. A complete list of the investigators and contributors to the INTERVAL trial has previously been provided [Di Angelantonio E, Thompson SG, Kaptoge S, Moore C, Walker M, Armitage J et al. Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomized trial of 45 000 donors. Lancet. 2017;390(10110):2360-71.]. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. The Genotype-Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (NIH). Additional funds from the National Cancer Institute; National Human Genome Research Institute (NHGRI); National Heart, Lung, and Blood Institute; National Institute on Drug Abuse; National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. The authors would like to thank the staff at the IUCPQ Biobank of the Quebec Respiratory Heath Research Network for their valuable assistance with the lung eQTL dataset at Laval University. Publisher Copyright: © 2020 The Authors.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10 -4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.
AB - Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10 -4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.
KW - COVID-19
KW - Mendelian randomization
KW - angiotensin-converting enzyme inhibitors
KW - genetic epidemiology
UR - http://www.scopus.com/inward/record.url?scp=85091304539&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091304539&partnerID=8YFLogxK
U2 - 10.1098/rsos.200958
DO - 10.1098/rsos.200958
M3 - Article
C2 - 33391794
AN - SCOPUS:85091304539
SN - 2054-5703
VL - 7
JO - Royal Society Open Science
JF - Royal Society Open Science
IS - 11
M1 - 0958
ER -