Evaluating the effects of cardiometabolic exposures on circulating proteins which may contribute to severe SARS-CoV-2.
Cardiometabolic risk factors
Circulating proteins
Covid19
Mendelian randomization
SARS-CoV-2
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Feb 2021
Feb 2021
Historique:
received:
29
09
2020
revised:
14
12
2020
accepted:
13
01
2021
pubmed:
7
2
2021
medline:
9
3
2021
entrez:
6
2
2021
Statut:
ppublish
Résumé
Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease 2019 (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2. We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence severe SARS-CoV-2. In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyzes. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P = 2.19 × 10 Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 infection or covid-19 progression are warranted to help elucidate therapeutic strategies for severe covid-19 disease. The Medical Research Council, the Wellcome Trust, the British Heart Foundation and UK Research and Innovation.
Sections du résumé
BACKGROUND
BACKGROUND
Developing insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to overcome the global pandemic caused by coronavirus disease 2019 (covid-19). In this study, we have applied Mendelian randomization (MR) to systematically evaluate the effect of 10 cardiometabolic risk factors and genetic liability to lifetime smoking on 97 circulating host proteins postulated to either interact or contribute to the maladaptive host response of SARS-CoV-2.
METHODS
METHODS
We applied the inverse variance weighted (IVW) approach and several robust MR methods in a two-sample setting to systemically estimate the genetically predicted effect of each risk factor in turn on levels of each circulating protein. Multivariable MR was conducted to simultaneously evaluate the effects of multiple risk factors on the same protein. We also applied MR using cis-regulatory variants at the genomic location responsible for encoding these proteins to estimate whether their circulating levels may influence severe SARS-CoV-2.
FINDINGS
RESULTS
In total, we identified evidence supporting 105 effects between risk factors and circulating proteins which were robust to multiple testing corrections and sensitivity analyzes. For example, body mass index provided evidence of an effect on 23 circulating proteins with a variety of functions, such as inflammatory markers c-reactive protein (IVW Beta=0.34 per standard deviation change, 95% CI=0.26 to 0.41, P = 2.19 × 10
INTERPRETATION
CONCLUSIONS
Our findings highlight several key proteins which are influenced by established exposures for disease. Future research to determine whether these circulating proteins mediate environmental effects onto risk of SARS-CoV-2 infection or covid-19 progression are warranted to help elucidate therapeutic strategies for severe covid-19 disease.
FUNDING
BACKGROUND
The Medical Research Council, the Wellcome Trust, the British Heart Foundation and UK Research and Innovation.
Identifiants
pubmed: 33548839
pii: S2352-3964(21)00021-9
doi: 10.1016/j.ebiom.2021.103228
pmc: PMC7857697
pii:
doi:
Substances chimiques
Biomarkers
0
IL6 protein, human
0
Interleukin-1
0
Interleukin-6
0
C-Reactive Protein
9007-41-4
Types de publication
Evaluation Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103228Subventions
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S003886/1
Pays : United Kingdom
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests Dr Holmes has collaborated with Boehringer Ingelheim in research, and in adherence to the University of Oxford's Clinical Trial Service Unit & Epidemiological Studies Unit (CSTU) staff policy, did not accept personal honoraria or other payments from pharmaceutical companies. All other authors declare no conflicts of interest.
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