Response to Comment on Baranova et al. Causal Associations Between Basal Metabolic Rate and COVID-19. Diabetes 2023;72:149–154

Kloecker, Brage, and Wareham (1) have provided an important argument in the discussion of major metabolic correlates of the incidence and the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Indeed, as individuals with obesity have a higher basal metabolic rate (BMR) than lean control individuals (2), an increase in susceptibility to and severity of coronavirus disease 2019 (COVID-19) at higher BMR is not surprising. As BMR prediction equations rely on BMI and body composition measurements, there is a risk that the conclusions of our study will be called trivial and merely a repeat of previous findings that describe obesity as an important contributor to phenotypes of COVID-19.

To mitigate this risk, we have taken Mendelian randomization (MR) analysis one step further by running a secondary analysis by utilizing the multivariable MR (MVMR) framework (3), which allows us to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding factors, i.e., BMI (4). In MVMR, accounting for BMI and type 2 diabetes diminished the significance of the observed causal association of BMR with severe COVID-19, indicating that overweight and obesity, indeed, explain this finding. Nevertheless, an association of BMR with an increased risk for SARS-CoV-2 infection continued to be noticeable (odds ratio 1.09, CI 1.03–1.15, P = 4.82E−03) after similar adjustments were made, indicating that the predictors for BMR selected by UK Biobank can capture more than the BMI or the diabetes-related components. Most likely, genetic variation that contributes to BMR but neither BMI nor type 2 diabetes reflects preexisting dysfunction of the steady-state level of energy homeostasis, including “classical” types of inflammation, for example, the ones caused by bacterial infections and mechanical tissue injury, rather than the systemic inflammation underlining diabetes and obesity.

Altogether, the findings of our study point out that there is more to BMR than it seems, and its relationship with COVID-19 outcomes might be less trivial than expected.