COL6A3-derived endotrophin mediates the effect of obesity on coronary artery disease: an integrative proteogenomics analysis

Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity has broad effects on circulating protein levels, we investigated circulating proteins that mediate the effects of obesity on coronary artery disease (CAD), stroke, and type 2 diabetes--since doing so may prioritize targets for therapeutic intervention. By integrating proteome-wide Mendelian randomization (MR) screening 4,907 plasma proteins, colocalization, and mediation analyses, we identified seven plasma proteins, including collagen type VI 3 (COL6A3). COL6A3 was strongly increased by body mass index (BMI) ({beta} = 0.32, 95% CI: 0.26-0.38, P = 3.7 x 10-8 per s.d. increase in BMI) and increased the risk of CAD (OR = 1.47, 95% CI:1.26-1.70, P = 4.5 x 10-7 per s.d. increase in COL6A3). Notably, COL6A3 is cleaved at its C-terminus to produce endotrophin, which was found to mediate this effect on CAD. In single-cell RNA sequencing of adipose tissues and coronary arteries, COL6A3 was highly expressed in cell types involved in metabolic dysfunction and fibrosis. Finally, we found that body fat reduction can reduce plasma levels of COL6A3-derived endotrophin, thereby highlighting a tractable way to modify endotrophin levels. In summary, we provide actionable insights into how circulating proteins mediate the effect of obesity on cardiometabolic diseases and prioritize endotrophin as a potential therapeutic target.