Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study

Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding l...

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Published in:	PLoS medicine Vol. 20; no. 1; p. e1004174
Main Authors:	Hamilton, Fergus W., Thomas, Matt, Arnold, David, Palmer, Tom, Moran, Ed, Mentzer, Alexander J., Maskell, Nick, Baillie, Kenneth, Summers, Charlotte, Hingorani, Aroon, MacGowan, Alasdair, Khandaker, Golam M., Mitchell, Ruth, Davey Smith, George, Ghazal, Peter, Timpson, Nicholas J.
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 30.01.2023 Public Library of Science (PLoS)
Subjects:	Analysis Biobanks Biology and Life Sciences Cardiovascular disease Care and treatment Chromosomes Consortia Coronaviruses COVID-19 Critical care Cytokines Dosage and administration Genetic diversity Genetics Glycoprotein gp130 Health aspects Hospitalization Humans Immune response Infection Infections Interleukin 6 Interleukin 6 receptors Interleukin-6 - genetics Interleukins Medicine and Health Sciences Mendelian Randomization Analysis Monoclonal antibodies Mortality Patient outcomes Physical Sciences Proteins Quality control Receptors, Interleukin-6 - genetics Research and Analysis Methods Sensitivity analysis Sepsis Sepsis - drug therapy Sepsis - genetics Single nucleotide polymorphisms Single-nucleotide polymorphism Statistics Survival Testing United Kingdom United Kingdom > UK
ISSN:	1549-1676, 1549-1277, 1549-1676
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Abstract	Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.
AbstractList	Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. We performed a mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered. BackgroundSepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.Methods and findingsWe performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.ConclusionsIL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered. Background Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods and findings We performed a mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered. In a Mendelian randomisation analysis, Fergus Hamilton and colleagues test the hypothesis that blockade of interleukin-6 signalling could improve outcomes in sepsis. Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.BACKGROUNDSepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis.We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.METHODS AND FINDINGSWe performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade.IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.CONCLUSIONSIL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered. Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered. Background Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic variants in IL6R known to down-regulate IL-6 signalling are associated with improved Coronavirus Disease 2019 (COVID-19) outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RAs). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods and findings We performed a Mendelian randomisation (MR) analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis (primary outcome), sepsis severity, other infections, and COVID-19 (secondary outcomes). We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP and gp130 in a similar analysis. In the UK Biobank cohort (N = 486,484, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of our primary outcome, sepsis (odds ratio (OR) = 0.80; 95% confidence interval (CI) 0.66 to 0.96, per unit of natural log-transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR = 0.74; 95% CI 0.47 to 1.15); critical care admission with sepsis (OR = 0.48, 95% CI 0.30 to 0.78) and critical care death with sepsis (OR = 0.37, 95% CI 0.14 to 0.98). Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 to 0.97) and for sepsis survival in critical care (OR = 0.22; 95% CI 0.04 to 1.31) in the GainS and GenOSept consortium, although this result had a large degree of imprecision. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR = 0.69, 95% CI 0.57 to 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. These results are subject to the limitations and assumptions of MR, which in this case reflects interpretation of these SNP effects as causally acting through blockade of IL6R, and reflect lifetime exposure to IL6R blockade, rather than the effect of therapeutic IL6R blockade. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis. Similar but imprecisely estimated results supported a causal effect also on sepsis related mortality and critical care admission with sepsis. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. These data suggest that a randomised trial of IL-6 receptor antagonists in sepsis should be considered.
Audience	Academic
Author	Timpson, Nicholas J. Khandaker, Golam M. Thomas, Matt MacGowan, Alasdair Baillie, Kenneth Ghazal, Peter Mitchell, Ruth Hamilton, Fergus W. Maskell, Nick Davey Smith, George Moran, Ed Mentzer, Alexander J. Palmer, Tom Arnold, David Summers, Charlotte Hingorani, Aroon
AuthorAffiliation	4 Academic Respiratory Unit, University of Bristol, Bristol, United Kingdom 7 Department of Medicine, University of Cambridge, Cambridge, United Kingdom 6 Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom 8 UCL Institute for Cardiovascular Science, University College London, London, United Kingdom 1 MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom 9 UCL BHF Research Accelerator, University College London, London, United Kingdom 11 Project Sepsis, Cardiff University, Cardiff, United Kingdom Imperial College London, UNITED KINGDOM 2 Infection Science, North Bristol NHS Trust, Bristol, United Kingdom 5 Wellcome Centre For Human Genetics, University of Oxford, Oxford, United Kingdom 10 Health Data Research UK, London, United Kingdom 3 Intensive Care Unit, North Bristol NHS Trust, Bristol, United Kingdom
AuthorAffiliation_xml	– name: 4 Academic Respiratory Unit, University of Bristol, Bristol, United Kingdom – name: 3 Intensive Care Unit, North Bristol NHS Trust, Bristol, United Kingdom – name: 8 UCL Institute for Cardiovascular Science, University College London, London, United Kingdom – name: 1 MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom – name: 10 Health Data Research UK, London, United Kingdom – name: 7 Department of Medicine, University of Cambridge, Cambridge, United Kingdom – name: 9 UCL BHF Research Accelerator, University College London, London, United Kingdom – name: Imperial College London, UNITED KINGDOM – name: 11 Project Sepsis, Cardiff University, Cardiff, United Kingdom – name: 6 Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom – name: 2 Infection Science, North Bristol NHS Trust, Bristol, United Kingdom – name: 5 Wellcome Centre For Human Genetics, University of Oxford, Oxford, United Kingdom
Author_xml	– sequence: 1 givenname: Fergus W. orcidid: 0000-0002-9760-4059 surname: Hamilton fullname: Hamilton, Fergus W. – sequence: 2 givenname: Matt orcidid: 0000-0002-3407-6762 surname: Thomas fullname: Thomas, Matt – sequence: 3 givenname: David surname: Arnold fullname: Arnold, David – sequence: 4 givenname: Tom orcidid: 0000-0003-4655-4511 surname: Palmer fullname: Palmer, Tom – sequence: 5 givenname: Ed surname: Moran fullname: Moran, Ed – sequence: 6 givenname: Alexander J. orcidid: 0000-0002-4502-2209 surname: Mentzer fullname: Mentzer, Alexander J. – sequence: 7 givenname: Nick surname: Maskell fullname: Maskell, Nick – sequence: 8 givenname: Kenneth surname: Baillie fullname: Baillie, Kenneth – sequence: 9 givenname: Charlotte orcidid: 0000-0002-7269-2873 surname: Summers fullname: Summers, Charlotte – sequence: 10 givenname: Aroon surname: Hingorani fullname: Hingorani, Aroon – sequence: 11 givenname: Alasdair surname: MacGowan fullname: MacGowan, Alasdair – sequence: 12 givenname: Golam M. surname: Khandaker fullname: Khandaker, Golam M. – sequence: 13 givenname: Ruth surname: Mitchell fullname: Mitchell, Ruth – sequence: 14 givenname: George surname: Davey Smith fullname: Davey Smith, George – sequence: 15 givenname: Peter orcidid: 0000-0003-0035-2228 surname: Ghazal fullname: Ghazal, Peter – sequence: 16 givenname: Nicholas J. orcidid: 0000-0002-7141-9189 surname: Timpson fullname: Timpson, Nicholas J.
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Cites_doi	10.1016/S0140-6736(20)30920-X 10.1038/oby.2007.28 10.1016/j.humimm.2010.10.010 10.1161/CIRCULATIONAHA.120.052604 10.1016/j.molmed.2014.01.007 10.1016/S0140-6736(12)60110-X 10.1038/s41586-021-03767-x 10.1016/S2213-2600(14)70290-5 10.1038/s41588-021-00978-w 10.1038/s41467-022-29650-5 10.1093/ije/dyy101 10.1016/S0140-6736(21)00520-1 10.1001/jama.2021.11330 10.1001/jamapsychiatry.2020.3436 10.1136/bmj.d548 10.1161/CIRCGEN.119.002872 10.1056/NEJMoa2100433 10.1371/journal.pone.0187015 10.1016/j.bbi.2021.02.019 10.1111/bcp.15191 10.1001/archinte.167.15.1655 10.1038/s43586-021-00092-5 10.1093/ije/dyt093 10.1016/j.cyto.2021.155690 10.1371/journal.pgen.1003444 10.1056/NEJMra1208623 10.1161/JAHA.121.023277 10.1002/jcph.185 10.12688/wellcomeopenres.16544.1 10.1016/S2665-9913(20)30345-3 10.1038/s41586-018-0579-z 10.7554/eLife.34408 10.1016/S0140-6736(21)00676-0 10.3389/fimmu.2022.860703 10.1371/journal.pgen.1009975 10.1038/s41588-021-00870-7 10.1016/0002-9343(91)90069-A 10.1371/journal.pmed.1003898 10.1016/j.jacbts.2021.01.013 10.1128/IAI.73.5.2751-2757.2005 10.1038/nature04672 10.1038/s41380-019-0395-3 10.1038/s41591-021-01371-0 10.1136/bmj.n2233 10.1097/CCE.0000000000000364 10.1097/CCE.0000000000000387
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References	GM Khandaker (pmed.1004174.ref017) 2020; 25 MB Pepys (pmed.1004174.ref043) 2006; 440 Swerdlow DI Consortium (pmed.1004174.ref016) 2012; 379 C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) (pmed.1004174.ref036) 2011; 342 DC Angus (pmed.1004174.ref001) 2013; 369 D Gill (pmed.1004174.ref020) 2022; 19 H Li (pmed.1004174.ref023) 2020; 395 S Ohta (pmed.1004174.ref013) 2014; 54 JC Marshall (pmed.1004174.ref002) 2014; 20 L Gottardo (pmed.1004174.ref038) 2008; 16 MK Georgakis (pmed.1004174.ref019) 2022; 11 RECOVERY Collaborative Group (pmed.1004174.ref009) 2021; 397 A Rautanen (pmed.1004174.ref027) 2015; 3 M Zhang (pmed.1004174.ref049) 2022; 13 J Mbatchou (pmed.1004174.ref029) 2021; 53 E Sanderson (pmed.1004174.ref021) 2022; 2 E Ferkingstad (pmed.1004174.ref039) 2021; 53 S. Rose-John (pmed.1004174.ref008) 2021; 148 J Bovijn (pmed.1004174.ref015) 2020; 2 A Rantala (pmed.1004174.ref046) 2011; 72 G Hemani (pmed.1004174.ref035) 2018; 7 AJ Grant (pmed.1004174.ref041) 2022; 18 T Calandra (pmed.1004174.ref005) 1991; 91 MJ George (pmed.1004174.ref044) 2021; 6 MK Georgakis (pmed.1004174.ref050) 2021; 143 VW Skrivankova (pmed.1004174.ref042) 2021; 375 CHARGE Inflammation Working Group (pmed.1004174.ref031) 2022; 88 PM Ridker (pmed.1004174.ref012) 2021; 397 SM Zekavat (pmed.1004174.ref028) 2021; 27 S Burgess (pmed.1004174.ref034) 2013; 42 R Yamamoto (pmed.1004174.ref006) 2021; 3 DG Remick (pmed.1004174.ref003) 2005; 73 COVID-19 Host Genetics Initiative (pmed.1004174.ref026) 2021; 600 SC Larsson (pmed.1004174.ref014) 2021 Z Ye (pmed.1004174.ref032) 2021 S Said (pmed.1004174.ref037) 2022; 13 WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group (pmed.1004174.ref011) 2021; 326 S. Rose-John (pmed.1004174.ref007) 2018 D Gill (pmed.1004174.ref051) 2021; 6 RC Ferreira (pmed.1004174.ref022) 2013; 9 D Schädler (pmed.1004174.ref048) 2017; 12 C Bycroft (pmed.1004174.ref024) 2018; 562 MI Kurki (pmed.1004174.ref025) 2022 R Mitchell (pmed.1004174.ref030) 2019 REMAP-CAP Investigators (pmed.1004174.ref010) 2021; 384 MS Rizvi (pmed.1004174.ref047) 2021; 3 MK Georgakis (pmed.1004174.ref033) 2020; 13 KM Kelly (pmed.1004174.ref045) 2021; 95 JA Kellum (pmed.1004174.ref004) 2007; 167 N Kappelmann (pmed.1004174.ref018) 2021; 78 J Bowden (pmed.1004174.ref040) 2018; 47
References_xml	– volume: 395 start-page: 1517 year: 2020 ident: pmed.1004174.ref023 article-title: SARS-CoV-2 and viral sepsis: observations and hypotheses publication-title: Lancet doi: 10.1016/S0140-6736(20)30920-X – volume: 16 start-page: 205 year: 2008 ident: pmed.1004174.ref038 article-title: A polymorphism at the IL6ST (gp130) locus is associated with traits of the metabolic syndrome. publication-title: Obesity doi: 10.1038/oby.2007.28 – volume: 72 start-page: 63 year: 2011 ident: pmed.1004174.ref046 article-title: Association of IL-6 and IL-6R gene polymorphisms with susceptibility to respiratory tract infections in young Finnish men publication-title: Hum Immunol doi: 10.1016/j.humimm.2010.10.010 – volume: 143 start-page: 1177 year: 2021 ident: pmed.1004174.ref050 article-title: Genetically Downregulated Interleukin-6 Signaling Is Associated With a Favorable Cardiometabolic Profile: A Phenome-Wide Association Study publication-title: Circulation doi: 10.1161/CIRCULATIONAHA.120.052604 – volume: 20 start-page: 195 year: 2014 ident: pmed.1004174.ref002 article-title: Why have clinical trials in sepsis failed? publication-title: Trends Mol Med doi: 10.1016/j.molmed.2014.01.007 – volume: 379 start-page: 1214 year: 2012 ident: pmed.1004174.ref016 article-title: The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. publication-title: Lancet doi: 10.1016/S0140-6736(12)60110-X – volume: 600 start-page: 472 year: 2021 ident: pmed.1004174.ref026 article-title: Mapping the human genetic architecture of COVID-19. publication-title: Nature doi: 10.1038/s41586-021-03767-x – volume: 3 start-page: 53 year: 2015 ident: pmed.1004174.ref027 article-title: Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study publication-title: Lancet Respir Med doi: 10.1016/S2213-2600(14)70290-5 – volume: 53 start-page: 1712 year: 2021 ident: pmed.1004174.ref039 article-title: Large-scale integration of the plasma proteome with genetics and disease publication-title: Nat Genet doi: 10.1038/s41588-021-00978-w – volume: 13 start-page: 2198 year: 2022 ident: pmed.1004174.ref037 article-title: Genetic analysis of over half a million people characterises C-reactive protein loci publication-title: Nat Commun doi: 10.1038/s41467-022-29650-5 – volume: 47 start-page: 1264 year: 2018 ident: pmed.1004174.ref040 article-title: Improving the visualization, interpretation and analysis of two-sample summary data Mendelian randomization via the Radial plot and Radial regression. publication-title: Int J Epidemiol doi: 10.1093/ije/dyy101 – volume: 397 start-page: 2060 year: 2021 ident: pmed.1004174.ref012 article-title: IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. publication-title: Lancet doi: 10.1016/S0140-6736(21)00520-1 – volume: 326 start-page: 499 year: 2021 ident: pmed.1004174.ref011 article-title: Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. publication-title: JAMA doi: 10.1001/jama.2021.11330 – volume: 78 start-page: 161 year: 2021 ident: pmed.1004174.ref018 article-title: Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms: A Genetic Correlation and 2-Sample Mendelian Randomization Study. publication-title: JAMA Psychiat. doi: 10.1001/jamapsychiatry.2020.3436 – volume: 342 start-page: d548 year: 2011 ident: pmed.1004174.ref036 article-title: Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. publication-title: BMJ doi: 10.1136/bmj.d548 – start-page: 10 year: 2018 ident: pmed.1004174.ref007 article-title: Interleukin-6 Family Cytokines publication-title: Cold Spring Harb Perspect Biol – volume: 13 start-page: e002872 year: 2020 ident: pmed.1004174.ref033 article-title: Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes. publication-title: Circ Genom Precis Med doi: 10.1161/CIRCGEN.119.002872 – volume: 384 start-page: 1491 year: 2021 ident: pmed.1004174.ref010 article-title: Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 publication-title: N Engl J Med doi: 10.1056/NEJMoa2100433 – volume: 12 start-page: e0187015 year: 2017 ident: pmed.1004174.ref048 article-title: The effect of a novel extracorporeal cytokine hemoadsorption device on IL-6 elimination in septic patients: A randomized controlled trial. publication-title: PLoS ONE doi: 10.1371/journal.pone.0187015 – volume: 95 start-page: 106 year: 2021 ident: pmed.1004174.ref045 article-title: Depression and interleukin-6 signaling: A Mendelian Randomization study publication-title: Brain Behav Immun doi: 10.1016/j.bbi.2021.02.019 – volume: 88 start-page: 2875 year: 2022 ident: pmed.1004174.ref031 article-title: Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R publication-title: Br J Clin Pharmacol doi: 10.1111/bcp.15191 – volume: 167 start-page: 1655 year: 2007 ident: pmed.1004174.ref004 article-title: Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. publication-title: Arch Intern Med doi: 10.1001/archinte.167.15.1655 – volume: 2 start-page: 1 year: 2022 ident: pmed.1004174.ref021 article-title: Mendelian randomization. publication-title: Nature Reviews Methods Primers doi: 10.1038/s43586-021-00092-5 – volume: 42 start-page: 1134 year: 2013 ident: pmed.1004174.ref034 article-title: Use of allele scores as instrumental variables for Mendelian randomization. publication-title: Int J Epidemiol doi: 10.1093/ije/dyt093 – year: 2021 ident: pmed.1004174.ref032 article-title: Role of inflammation in depression and anxiety: Tests for disorder specificity, linearity and potential causality of association in the UK Biobank. publication-title: bioRxiv medRxiv; – volume: 148 start-page: 155690 year: 2021 ident: pmed.1004174.ref008 article-title: Blocking only the bad side of IL-6 in inflammation and cancer publication-title: Cytokine doi: 10.1016/j.cyto.2021.155690 – volume: 9 start-page: e1003444 year: 2013 ident: pmed.1004174.ref022 article-title: Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases publication-title: PLoS Genet doi: 10.1371/journal.pgen.1003444 – volume: 369 start-page: 840 year: 2013 ident: pmed.1004174.ref001 article-title: Severe sepsis and septic shock publication-title: N Engl J Med doi: 10.1056/NEJMra1208623 – volume: 11 start-page: e023277 year: 2022 ident: pmed.1004174.ref019 article-title: Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis publication-title: J Am Heart Assoc doi: 10.1161/JAHA.121.023277 – volume: 54 start-page: 109 year: 2014 ident: pmed.1004174.ref013 article-title: Mechanism-based approach using a biomarker response to evaluate tocilizumab subcutaneous injection in patients with rheumatoid arthritis with an inadequate response to synthetic DMARDs (MATSURI study). publication-title: J Clin Pharmacol doi: 10.1002/jcph.185 – year: 2019 ident: pmed.1004174.ref030 article-title: UK Biobank genetic data: MRC-IEU quality control, version 2 publication-title: University of Bristol – volume: 6 start-page: 16 year: 2021 ident: pmed.1004174.ref051 article-title: Mendelian randomization for studying the effects of perturbing drug targets. publication-title: Wellcome Open Res doi: 10.12688/wellcomeopenres.16544.1 – volume: 2 start-page: e658 year: 2020 ident: pmed.1004174.ref015 article-title: Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19. publication-title: Lancet Rheumatol. doi: 10.1016/S2665-9913(20)30345-3 – volume: 562 start-page: 203 year: 2018 ident: pmed.1004174.ref024 article-title: The UK Biobank resource with deep phenotyping and genomic data publication-title: Nature doi: 10.1038/s41586-018-0579-z – volume: 7 year: 2018 ident: pmed.1004174.ref035 article-title: The MR-Base platform supports systematic causal inference across the human phenome. publication-title: Elife doi: 10.7554/eLife.34408 – volume: 397 start-page: 1637 year: 2021 ident: pmed.1004174.ref009 article-title: Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. publication-title: Lancet doi: 10.1016/S0140-6736(21)00676-0 – volume: 13 start-page: 860703 year: 2022 ident: pmed.1004174.ref049 article-title: Cumulative Evidence for Associations Between Genetic Variants in Interleukin 6 Receptor Gene and Human Diseases and Phenotypes. publication-title: Front Immunol doi: 10.3389/fimmu.2022.860703 – volume: 18 start-page: e1009975 year: 2022 ident: pmed.1004174.ref041 article-title: Noise-augmented directional clustering of genetic association data identifies distinct mechanisms underlying obesity publication-title: PLoS Genet doi: 10.1371/journal.pgen.1009975 – volume: 53 start-page: 1097 year: 2021 ident: pmed.1004174.ref029 article-title: Computationally efficient whole-genome regression for quantitative and binary traits publication-title: Nat Genet doi: 10.1038/s41588-021-00870-7 – volume: 91 start-page: 23 year: 1991 ident: pmed.1004174.ref005 article-title: High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group publication-title: Am J Med doi: 10.1016/0002-9343(91)90069-A – volume: 19 start-page: e1003898 year: 2022 ident: pmed.1004174.ref020 article-title: The evolution of mendelian randomization for investigating drug effects publication-title: PLoS Med doi: 10.1371/journal.pmed.1003898 – year: 2022 ident: pmed.1004174.ref025 article-title: FinnGen: Unique genetic insights from combining isolated population and national health register data. publication-title: bioRxiv – volume: 6 start-page: 431 year: 2021 ident: pmed.1004174.ref044 article-title: Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction. publication-title: JACC Basic Transl Sci. doi: 10.1016/j.jacbts.2021.01.013 – volume: 73 start-page: 2751 year: 2005 ident: pmed.1004174.ref003 article-title: Role of interleukin-6 in mortality from and physiologic response to sepsis publication-title: Infect Immun doi: 10.1128/IAI.73.5.2751-2757.2005 – volume: 440 start-page: 1217 year: 2006 ident: pmed.1004174.ref043 article-title: Targeting C-reactive protein for the treatment of cardiovascular disease publication-title: Nature doi: 10.1038/nature04672 – volume: 25 start-page: 1477 year: 2020 ident: pmed.1004174.ref017 article-title: Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort publication-title: Mol Psychiatry doi: 10.1038/s41380-019-0395-3 – volume: 27 start-page: 1012 year: 2021 ident: pmed.1004174.ref028 article-title: Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection publication-title: Nat Med doi: 10.1038/s41591-021-01371-0 – start-page: 57 year: 2021 ident: pmed.1004174.ref014 article-title: Genetically proxied interleukin-6 receptor inhibition: opposing associations with COVID-19 and pneumonia publication-title: Eur Respir J – volume: 375 start-page: n2233 year: 2021 ident: pmed.1004174.ref042 article-title: Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. publication-title: BMJ doi: 10.1136/bmj.n2233 – volume: 3 start-page: e0364 year: 2021 ident: pmed.1004174.ref047 article-title: New Decade, Old Debate: Blocking the Cytokine Pathways in Infection-Induced Cytokine Cascade publication-title: Crit Care Explor doi: 10.1097/CCE.0000000000000364 – volume: 3 start-page: e0387 year: 2021 ident: pmed.1004174.ref006 article-title: Accuracy for Mortality Prediction With Additive Biomarkers Including Interleukin-6 in Critically Ill Patients: A Multicenter Prospective Observational Study. publication-title: Crit Care Explor. doi: 10.1097/CCE.0000000000000387
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Snippet	Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6). Genetic... Background Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6... In a Mendelian randomisation analysis, Fergus Hamilton and colleagues test the hypothesis that blockade of interleukin-6 signalling could improve outcomes in... BackgroundSepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6 (IL-6).... Background Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin 6...
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SubjectTerms	Analysis Biobanks Biology and Life Sciences Cardiovascular disease Care and treatment Chromosomes Consortia Coronaviruses COVID-19 Critical care Cytokines Dosage and administration Genetic diversity Genetics Glycoprotein gp130 Health aspects Hospitalization Humans Immune response Infection Infections Interleukin 6 Interleukin 6 receptors Interleukin-6 - genetics Interleukins Medicine and Health Sciences Mendelian Randomization Analysis Monoclonal antibodies Mortality Patient outcomes Physical Sciences Proteins Quality control Receptors, Interleukin-6 - genetics Research and Analysis Methods Sensitivity analysis Sepsis Sepsis - drug therapy Sepsis - genetics Single nucleotide polymorphisms Single-nucleotide polymorphism Statistics Survival Testing
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Title	Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study
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