Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease.

ABSTRACT: Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity strongly influences circulating protein levels, we investigated proteins mediating the effects of obesity on coronary artery disease, stroke and type 2 diabetes. By integrating two-step proteome-wide Mendelian randomization, colocalization, epigenomics and single-cell RNA sequencing, we identified five mediators and prioritized collagen type VI α3 (COL6A3). COL6A3 levels were strongly increased by body mass index and increased coronary artery disease risk. Notably, the carboxyl terminus product of COL6A3, endotrophin, drove this effect. COL6A3 was highly expressed in disease-relevant cell types and tissues. Finally, we found that bo

SUBMITTER: Yoshiji S 

PROVIDER: S-EPMC11821532 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature