Yoshiji S, Butler-Laporte G, Lu T, Willett JDS, Su CY, Nakanishi T, Morrison DR, Chen Y, Liang K, Hultström M, Ilboudo Y, Afrasiabi Z, Lan S, Duggan N, DeLuca C, Vaezi M, Tselios C, Xue X, Bouab M, Shi F, Laurent L, Münter HM, Afilalo M, Afilalo J, Mooser V, Timpson NJ, Zeberg H, Zhou S, Forgetta V, Farjoun Y, Richards JB
Nat Metab - (-) 1-17 [2023-02-20; online 2023-02-20]
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.