Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity.
Nat Metab
; 5(2): 248-264, 2023 02.
Article
in English
| MEDLINE | ID: covidwho-2287963
ABSTRACT
Obesity is a major risk factor for Coronavirus disease (COVID-19) severity; however, the mechanisms underlying this relationship are not fully understood. As obesity influences the plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity in humans. Here, we screened 4,907 plasma proteins to identify proteins influenced by body mass index using Mendelian randomization. This yielded 1,216 proteins, whose effect on COVID-19 severity was assessed, again using Mendelian randomization. We found that an s.d. increase in nephronectin (NPNT) was associated with increased odds of critically ill COVID-19 (OR = 1.71, P = 1.63 × 10-10). The effect was driven by an NPNT splice isoform. Mediation analyses supported NPNT as a mediator. In single-cell RNA-sequencing, NPNT was expressed in alveolar cells and fibroblasts of the lung in individuals who died of COVID-19. Finally, decreasing body fat mass and increasing fat-free mass were found to lower NPNT levels. These findings provide actionable insights into how obesity influences COVID-19 severity.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Proteome
/
COVID-19
/
Obesity
Type of study:
Experimental Studies
/
Prognostic study
Topics:
Long Covid
Limits:
Humans
Language:
English
Journal:
Nat Metab
Year:
2023
Document Type:
Article
Affiliation country:
S42255-023-00742-w
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