Cardiometabolic traits, sepsis and severe covid-19: a Mendelian randomization investigation
Authors: Ponsford Mark J , Gkatzionis Apostolos , Walker Venexia M , Grant Andrew J , Wootton Robyn E , Moore Luke S P , Fatumo Segun , Mason Amy M , Zuber Verena , Willer Cristen , Rasheed Humaira , Brumpton Ben , Hveem Kristian , Damås Jan Kristian , Davies Neil , Åsvold Bjørn Olav , Solligård Erik , Jones Simon , Burgess Stephen , Rogne Tormod , Gill Dipender 
Published: June 2020

AbstractObjectivesTo investigate whether there is a causal effect of cardiometabolic traits on risk of sepsis and severe covid-19.DesignMendelian randomisation analysis.SettingUK Biobank and HUNT study population-based cohorts for risk of sepsis, and genome-wide association study summary data for risk of severe covid-19 with respiratory failure.Participants12,455 sepsis cases (519,885 controls) and 1,610 severe covid-19 with respiratory failure cases (2,205 controls).ExposureGenetic variants that proxy body mass index (BMI), lipid traits, systolic blood pressure, lifetime smoking score, and type 2 diabetes liability - derived from studies considering between 188,577 to 898,130 participants.Main outcome measuresRisk of sepsis and severe covid-19 with respiratory failure.ResultsHigher genetically proxied BMI and lifetime smoking score were associated with increased risk of sepsis in both UK Biobank (BMI: odds ratio 1.38 per standard deviation increase, 95% confidence interval [CI] 1.27 to 1.51; smoking: odds ratio 2.81 per standard deviation increase, 95% CI 2.09-3.79) and HUNT (BMI: 1.41, 95% CI 1.18 to 1.69; smoking: 1.93, 95% CI 1.02-3.64). Higher genetically proxied BMI and lifetime smoking score were also associated with increased risk of severe covid-19, although with wider confidence intervals (BMI: 1.75, 95% CI 1.20 to 2.57; smoking: 3.94, 95% CI 1.13 to 13.75). There was limited evidence to support associations of genetically proxied lipid traits, systolic blood pressure or type 2 diabetes liability with risk of sepsis or severe covid-19. Similar findings were generally obtained when using Mendelian randomization methods that are more robust to the inclusion of pleiotropic variants, although the precision of estimates was reduced.ConclusionsOur findings support a causal effect of elevated BMI and smoking on risk of sepsis and severe covid-19. Clinical and public health interventions targeting obesity and smoking are likely to reduce sepsis and covid-19 related morbidity, along with the plethora of other health-related outcomes that these traits adversely affect.Summary boxesWhat is already known on this topicSepsis and severe covid-19 are major contributors to global morbidity and mortality.Cardiometabolic risk factors have been associated with risk of sepsis and severe covid-19, but it is unclear if they are having causal effects.What this study addsUsing Mendelian randomization analyses, this study provides evidence to support that higher body mass index and lifetime smoking score both increase risk of sepsis and severe covid-19 with respiratory failure.Clinical and public health interventions targeting obesity and smoking are likely to reduce sepsis and covid-19 related morbidity, along with the plethora of other health-related outcomes that these traits adversely affect.