TY - JOUR
T1 - Genetic risk for severe COVID-19 correlates with lower inflammatory marker levels in a SARS-CoV-2-negative cohort
AU - Powell, Timothy
AU - Hotopf, Matthew
AU - Hatch, Stephani
AU - Breen, Gerome
AU - Rafagnin Duarte, Rodrigo R
AU - Nixon, Douglas
N1 - Funding Information:
GB has received research funding from Eli Lilly. All other authors declare no relevant competing interests.
Funding Information:
We thank all participants of the SELCoH study. This study represents independent research part‐funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the UK Department of Health and Social Care. Research reported in this publication was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R21AI154956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We thank all participants of the SELCoH study. This study represents independent research part-funded by the NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King?s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the UK Department of Health and Social Care. Research reported in this publication was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R21AI154956. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.
PY - 2021/6/7
Y1 - 2021/6/7
N2 - Objectives: It remains unknown how inflammatory marker levels differ amongst individuals susceptible to coronavirus disease 2019 (COVID-19), prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the onset of the cytokine storm. We used genetic risk scores to model how susceptibility to severe COVID-19 correlates with baseline levels of 35 inflammatory markers, by testing their impact in a SARS-CoV-2-negative population cohort. Because of the established effects of age and body mass index on severe COVID-19 risk, we further considered how these variables interacted with genetic risk to affect inflammatory marker levels. Methods: We accessed data on 406 SARS-CoV-2-negative individuals as part of a UK population study. Multiplex electrochemiluminescence methods were applied to blood serum, and 35 inflammatory markers were assayed. Corresponding genotype data, alongside results from a large genome-wide association study of severe COVID-19, allowed us to construct genetic risk scores and to test their impact on inflammatory protein levels. Results: Our results revealed that a higher genetic risk for severe COVID-19 was associated with lower blood levels of interferon gamma (IFN-γ), vascular endothelial growth factor D (VEGF-D) and tumor necrosis factor alpha (TNF-α). Inflammatory profiles of those with high genetic risk increasingly diverge from the norm in association with age and obesity. Conclusion: Our results support the theory that individuals at risk of severe COVID-19 have a deficient innate immunity marked by reduced levels of inflammatory markers at baseline, including IFN-γ, VEGF-D and TNF-α. We hypothesise that a secondary overactive adaptive immune response may subsequently explain the high levels of cytokines observed in SARS-CoV-2-positive COVID-19 patients.
AB - Objectives: It remains unknown how inflammatory marker levels differ amongst individuals susceptible to coronavirus disease 2019 (COVID-19), prior to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the onset of the cytokine storm. We used genetic risk scores to model how susceptibility to severe COVID-19 correlates with baseline levels of 35 inflammatory markers, by testing their impact in a SARS-CoV-2-negative population cohort. Because of the established effects of age and body mass index on severe COVID-19 risk, we further considered how these variables interacted with genetic risk to affect inflammatory marker levels. Methods: We accessed data on 406 SARS-CoV-2-negative individuals as part of a UK population study. Multiplex electrochemiluminescence methods were applied to blood serum, and 35 inflammatory markers were assayed. Corresponding genotype data, alongside results from a large genome-wide association study of severe COVID-19, allowed us to construct genetic risk scores and to test their impact on inflammatory protein levels. Results: Our results revealed that a higher genetic risk for severe COVID-19 was associated with lower blood levels of interferon gamma (IFN-γ), vascular endothelial growth factor D (VEGF-D) and tumor necrosis factor alpha (TNF-α). Inflammatory profiles of those with high genetic risk increasingly diverge from the norm in association with age and obesity. Conclusion: Our results support the theory that individuals at risk of severe COVID-19 have a deficient innate immunity marked by reduced levels of inflammatory markers at baseline, including IFN-γ, VEGF-D and TNF-α. We hypothesise that a secondary overactive adaptive immune response may subsequently explain the high levels of cytokines observed in SARS-CoV-2-positive COVID-19 patients.
UR - http://www.scopus.com/inward/record.url?scp=85116856388&partnerID=8YFLogxK
U2 - 10.1002/cti2.1292
DO - 10.1002/cti2.1292
M3 - Article
VL - 10
SP - 1
EP - 10
JO - Clinical and Translational Immunology
JF - Clinical and Translational Immunology
IS - 6
M1 - e1292
ER -
