Researchers from McGill University’s Faculty of Medicine and Health Sciences based at the Lady Davis Institute of the Jewish General Hospital, have identified an actionable circulating protein that mediates the effect of obesity on COVID-19 severity.  

Obesity is a major risk factor for COVID-19 severity. However, the mechanisms underlying this relationship are not fully understood. The latest study published in Nature Metabolism used human genetics and proteomics to identify a circulating protein mediator of this relationship and showed that reducing body fat mass and increasing lean mass can lower the protein levels and reduce COVID-19 severity risk. 

The McGill study was led by principal investigator J. Brent Richards, MD, MSc, a Professor in Human Genetics, and Satoshi Yoshiji, MD, a physician-scientist trained in endocrinology. Dr. Yoshiji joined the Richards Lab as a PhD student in 2022. 

“COVID-19 has claimed more than 6.8 million lives worldwide, and we know obesity influences the risk of COVID-19, but we don’t know how,” explains Dr. Yoshiji. “We hypothesized that circulating protein may be mediating this relationship. Because they can be easily measured and can be often modulated, they are attractive targets. However, they’re involved in very complex biological systems. So we used a genetic epidemiology method called Mendelian randomization (MR) which allows researchers to do causal inference using genetic data. The aim of the study was to identify a circulating protein mediator and find a way to modulate it.”  

“In MR, we use genetic variants which are randomly allocated at conception. This resembles a randomized controlled trial (RCT), where drugs are randomly allocated, and you compare the outcome between two groups,” adds Dr. Yoshiji. “But in MR, instead of drugs, we use genetic variants that influence the exposure, for example BMI. We have a variant that increase BMI. And we have another variant which doesn’t increase BMI. Using these variants, we can evaluate the causal effect of BMI on the outcome, such as protein levels.” 

The research team performed MR analysis in a two-step manner. First, they sought to identify the effect of BMI, a proxy of obesity, on circulating protein levels. “We identified more than 1,200 proteins which are influenced by BMI. This means that BMI has a massive effect on circulating protein levels. So now we know what proteins are influenced by BMI,” Dr. Yoshiji notes. 

After identifying circulating proteins influenced by BMI, the researchers went on to look at the effect of BMI-driven proteins on COVID-19.  

In this second step, the team found a protein called nephronectin (NPNT) that arises as a mediator. “Of BMI-driven proteins, NPNT robustly increases the risk of COVID-19 severity. NPNT is a matrix protein that is highly expressed in your lung and this contributes to cell adhesion, which means that this protein is sticking your lungs together. In follow-up analyses, we analyzed lung tissues from patients who died of COVID-19, and we found that epithelial cells and fibroblast clusters highly expressed NPNT,” says Dr. Yoshiji. “These cell clusters play an important role in air exchange and fibrosis. This suggests NPNT could be involved in dysfunctional air exchange and fibrosis of COVID-19 patients. Finally, we asked if it could be modulated. Again, we used MR and found that decreasing fat mass and increasing lean mass leads to a decreased level of NPNT and subsequently a decrease in COVID severity. This means we can do something about this. We can decrease fat mass and increase lean mass through actions such as exercise or appropriate diet. We think this is very important because patients don’t have to wait for multiyear drug development. Instead, they can sign up for a gym and decrease their fat and increase their muscle to reduce their COVID severity risk.” 

There are likely to be other unexplored pathways that need further studies, Dr. Yoshiji notes, but for now he hopes this study helps the scientific and medical community tackle the ongoing pandemic. “We thank McGill and international collaborators and patients who contributed to the sample and data, particularly participants of BQC19 and the COVID Host Genetics Initiative.”