RESUMO
Obesity is a major risk factor for COVID-19 severity; however, the underlying mechanism is not fully understood. Considering that obesity influences the human plasma proteome, we sought to identify circulating proteins mediating the effects of obesity on COVID-19 severity. We first screened 4,907 plasma proteins to identify proteins influenced by body mass index (BMI) using Mendelian randomization (MR). This yielded 1,216 proteins, whose effects on COVID-19 severity were assessed, again using MR. This two-step approach identified nephronectin (NPNT), for which a one standard deviation increase was associated with severe COVID-19 (odds ratio = 1.71, 95% CI: 1.45-2.02, P = 1.63 x 10-10). Colocalization analyses indicated that an NPNT splice isoform drove this effect. Overall, NPNT mediates 3.7% of the total effect of BMI on severe COVID-19. Finally, we found that decreasing body fat mass and increasing fat-free mass can lower NPNT levels and thus may improve COVID-19 outcomes. These findings provide actionable insights into how obesity influences COVID-19 severity.
RESUMO
Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse COVID-19 outcomes in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4,701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different adverse COVID-19 outcomes were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of adverse COVID-19 outcomes. Further research is needed to understand how to incorporate protein measurement into clinical care.
RESUMO
Proteins detectable in peripheral blood may influence COVID-19 susceptibility or severity. However, understanding which circulating proteins are etiologically involved is difficult because their levels may be influenced by COVID-19 itself and are also subject to confounding factors. To identify circulating proteins influencing COVID-19 susceptibility and severity we undertook a large-scale two-sample Mendelian randomization (MR) study, since this study design can rapidly scan hundreds of circulating proteins and reduces bias due to reverse causation and confounding. We identified genetic determinants of 931 circulating proteins in 28,461 SARS-CoV-2 uninfected individuals, retaining only single nucleotide polymorphism near the gene encoding the circulating protein. We found that a standard deviation increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (N = 4,336 cases / 623,902 controls; OR = 0.54, P = 7x10-8), COVID-19 hospitalization (N = 6,406 / 902,088; OR = 0.61, P = 8x10-8) and COVID-19 susceptibility (N = 14,134 / 1,284,876; OR = 0.78, P = 8x10-6). Results were consistent in multiple sensitivity analyses. We then measured OAS1 levels in 504 patients with repeated plasma samples (N=1039) with different COVID-19 outcomes and found that increased OAS1 levels in a non-infectious state were associated with protection against very severe COVID-19, hospitalization and susceptibility. Further analyses suggested that a Neanderthal isoform of OAS1 affords this protection. Thus, evidence from MR and a case-control study supported a protective role for OAS1 in COVID-19 outcomes. Available medicines, such as phosphodiesterase-12 inhibitors, increase OAS1 and could be explored for their effect on COVID-19 susceptibility and severity.
