New research sheds light on potential therapeutic targets for cardiovascular disease prevention.
In a landmark study published in Nature Genetics, researchers from the Lady Davis Institute for Medical Research (LDI) at the Jewish General Hospital (JGH), in collaboration with international colleagues, have uncovered a crucial protein that may explain the long-observed connection between body mass index (BMI) and coronary artery disease (CAD). This discovery opens new avenues for potential treatments and underscores the complex relationship between obesity and heart health.
Led by Dr. Brent J. Richards, Senior Investigator at the LDI and Professor of Medicine in the Departments of Medicine (Endocrinology), Human Genetics, Epidemiology and Biostatistics at McGill University, and Satoshi Yoshiji, an Associate Investigator at the LDI and Assistant Professor in the Department of Human Genetics at McGill University, the study identified endotrophin, cleaved from C-terminal COL6A3, as a key mediator in the causal pathway linking increased BMI to higher CAD risk. The study suggests that reducing body fat can lower endotrophin levels, thereby decreasing CAD risk, and highlights endotrophin as a promising drug target.
“Our findings represent a significant step forward in understanding how excess body weight contributes to heart disease,” said Dr. Richards. “By pinpointing C-terminal COL6A3 as a critical player, we’ve opened up exciting possibilities for targeted interventions.”
The research team employed a sophisticated approach called Mendelian randomization, which uses genetic variations to infer causal relationships. This method allowed them to identify proteins that may mediate the effect of BMI on CAD risk, with C-terminal COL6A3 emerging as a prime candidate.
Satoshi Yoshiji, the study’s first author, emphasized the potential implications: “While we’ve made substantial progress, it’s crucial to note that this is just the beginning. Our work lays the foundation for future studies and clinical trials that could explore ways to modulate endotrophin as a potential therapeutic strategy.”
The study also highlighted several limitations, including its focus on individuals of European genetic ancestry, which underscores the need for further research across diverse populations. It also warrants new therapeutics that can selectively lower endotrophin levels.
Brent Richards added, “We’re at an exciting juncture where basic science meets clinical potential. The next steps involve translating these findings into practical applications that could benefit patients at risk of heart disease.”
“This research not only advances our understanding of the obesity-heart disease connection but also exemplifies the power of genetic and proteomic approaches in unraveling complex health issues. As obesity rates continue to rise globally, such insights could prove invaluable in developing targeted preventive strategies and treatments,” concluded Satoshi Yoshiji.
Yoshiji S, Lu T, Butler-Laporte G, Carrasco-Zanini-Sanchez J, Su CY, Chen Y, Liang K, Willett JDS, Wang S, Adra D, Ilboudo Y, Sasako T, Koyama S, Nakao T, Forgetta V, Farjoun Y, Zeberg H, Zhou S, Marks-Hultström M, Machiela MJ, Kaalia R, Dashti H, Claussnitzer M, Flannick J, Wareham NJ, Mooser V, Timpson NJ, Langenberg C, Richards JB. Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease. Nat Genet. 2025 Jan 24. doi: 10.1038/s41588-024-02052-7. Epub ahead of print. PMID: 39856218.
