Cardiometabolic traits, sepsis and severe covid-19: a Mendelian randomization investigation

  1. Mark J Ponsford
  2. Apostolos Gkatzionis
  3. Venexia M Walker
  4. Andrew J Grant
  5. Robyn E Wootton
  6. Luke S P Moore
  7. Segun Fatumo
  8. Amy M Mason
  9. Verena Zuber
  10. Cristen Willer
  11. Humaira Rasheed
  12. Ben Brumpton
  13. Kristian Hveem
  14. Jan Kristian Damås
  15. Neil Davies
  16. Bjørn Olav Åsvold
  17. Erik Solligård
  18. Simon Jones
  19. Stephen Burgess
  20. Tormod Rogne
  21. Dipender Gill
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Abstract

Objectives

To investigate whether there is a causal effect of cardiometabolic traits on risk of sepsis and severe covid-19.

Design

Mendelian randomisation analysis.

Setting

UK 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.

Participants

12,455 sepsis cases (519,885 controls) and 1,610 severe covid-19 with respiratory failure cases (2,205 controls).

Exposure

Genetic 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 measures

Risk of sepsis and severe covid-19 with respiratory failure.

Results

Higher 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.

Conclusions

Our 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 boxes

What is already known on this topic

  • Sepsis 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 adds

  • Using 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.

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