key: cord-0772334-bme2tar6
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; Kristian Damås, Jan; Davies, Neil; Olav Åsvold, Bjørn; Solligård, Erik; Jones, Simon; Burgess, Stephen; Rogne, Tormod; Gill, Dipender
title: Cardiometabolic Traits, Sepsis, and Severe COVID-19: A Mendelian Randomization Investigation
date: 2020-09-23
journal: Circulation
DOI: 10.1161/circulationaha.120.050753
sha: 9bbc298294401d1bb18f64d6082dc2e4f3a8496b
doc_id: 772334
cord_uid: bme2tar6

nan

CORRESPONDENCE lifetime smoking score were also associated with increased risk of severe COVID-19 with respiratory failure and hospitalization with COVID-19 ( Figure) . Similar estimates were obtained in MR sensitivity analyses, although with wider 95% CIs (Figure) . There was no strong evidence supporting an association of genetically proxied low-density lipoprotein cholesterol, systolic blood pressure, or T2DM liability with risk of sepsis or severe COVID-19.

Taken together, our findings support the hypothesis that elevated BMI and smoking increase susceptibility to sepsis and severe COVID-19. Many potential mechanisms may be underlying this causal relationship, especially immune dysregulation. 5 Furthermore, obesity and smoking status are both modifiable traits that may be targeted to reduce COVID-19-associated morbidity and mortality.

Our study has many strengths. We considered distinct data sources and performed MR methods that vary in their requisite assumptions about the inclusion of pleiotropic variants. Although the results were consistent, particular methods produced wider CIs than others, in keeping with known differences in their statistical power. 4 Furthermore, we considered COVID-19 cases that were severe enough to require hospitalization, and as such there was less risk of selection bias related to COVID-19 diagnosis, as all such patients would be expected to undergo testing.

Our study also has limitations. Our investigation was based on European ancestry participants.

Initiatives to identify genetic factors related to risk of severe COVID-19 are ongoing, 3 and such work will also expand to other ethnic groups. It is important to appreciate that MR effect estimates should not be directly extrapolated to predict the effect of an intervention, but should rather be used as evidence to support a causal relationship. Although we explored the association of genetically proxied T2DM liability with risk of sepsis and severe COVID-19, we were not able to assess the effect of a clinical T2DM diagnosis directly, because for most individuals presence of these genetic variants does not necessarily result in a T2DM diagnosis. Thus, there may be a causal relationship between diabetes (or glycemic control) and severe COVID-19 that our study could not detect. Our analyses also had limited statistical power, as apparent from the CIs of the results. Given that the genetic variants used to proxy systolic blood pressure, lowdensity lipoprotein cholesterol, and T2DM explained 2.9%, 7.9%, and 16.3% of the variance in these traits, respectively, 1 our main MR analysis had 80% power to detect an odds ratio for hospitalization with COVID-19 of 1.29 for systolic blood pressure, 1.18 for low-density lipoprotein cholesterol, and 1.12 for T2DM liability.

In conclusion, we leveraged large-scale genetic summary data to investigate the effects of cardiometabolic traits on risk of sepsis and severe COVID-19. Our findings support causal effects of elevated BMI and smoking on susceptibility to sepsis and severe COVID-19. Results are expressed per SD increase in genetically proxied levels of the exposure for continuous traits (BMI, LDL-C, SBP, and smoking), and per unit increase in log odds ratio for genetically proxied T2DM liability. The MR-Egger intercept P value was >0.05 for all analyses. BMI indicates body mass index; IVW, inversevariance weighted Mendelian randomization; LDL-C, low-density lipoprotein cholesterol; median, weighted median MR; SBP, systolic blood pressure; smoking, lifetime smoking score; and T2DM, type 2 diabetes.

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

Genome-wide association study of severe Covid-19 with respiratory failure

The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic

A comparison of robust Mendelian randomization methods using summary data

Obesity is a risk factor for severe COVID-19 infection: multiple potential mechanisms

Drs Gill, Burgess, and Ponsford designed the project. Drs Walker, Davies, Åsvold, Solligård, and Rogne provided the data. Drs Rogne, Walker, Gkatzionis, Fatumo, and Gill analyzed the data. Drs Ponsford, Gkatzionis, Walker, Grant, Fatumo, Rogne, and Gill drafted the article. All authors interpreted the results and critically revised the article for intellectual content. This research was con-