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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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 body fat reduction could reduce plasma levels of COL6A3-derived endotrophin, indicating a tractable way to modify endotrophin levels. In summary, we provide actionable insights into how circulating proteins mediate the effects of obesity on cardiometabolic diseases and prioritize endotrophin as a potential therapeutic target.

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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