THU582 Actionable Circulating Proteins Mediate The Effect Of Obesity On Cardiometabolic Diseases: An Integrative Proteogenomics Analysis

Disclosure: S. Yoshiji: None. T. Lu: Employee; Self; 5 Prime Sciences. G. Butler-Laporte: None. J. Carrasco-Zanini-Sanchez: None. Y. Chen: None. K. Liang: None. J.D. Willett: None. C. Su: None. S. Wang: Employee; Self; SomaLogic. D. Adra: None. Y. Ilbudo: None. S. Takayoshi: None. V. Forgetta: None. Y. Farjoun: Employee; Self; Fulcrum Genomics. H. Zeberg: None. S. Zhou: None. M. Machiela: None. M. Hultstrom: None. N. Wareham: None. N.J. Timpson: None. V. Mooser: None. C. Langenberg: None. B. Richards: Advisory Board Member; Self; GlaxoSmithKline. Owner/Co-Owner; Self; 5 Prime Sciences. Background: Obesity strongly increases the risk of cardiometabolic diseases; however, the underlying mediators of this relationship are not fully understood. As obesity strongly influences the plasma proteome, one strategy to disentangle this relationship is to identify plasma proteins mediating this relationship in humans. Since plasma proteins can be measured and in some cases modulated, they may offer attractive therapeutic targets. Aims: To identify plasma proteins mediating the relationship between obesity and coronary artery disease, stroke, and type 2 diabetes using an integrative analysis of proteome-wide Mendelian randomization (MR), statistical colocalization, mediation analyses, and single-cell RNA sequencing. Results: We screened 4,907 plasma proteins to identify proteins influenced by body mass index (BMI) with MR, wherein we used genome-wide association studies in up to one million individuals to make causal inference. This identified 2,714 BMI-influenced proteins (false discovery rate <0.5%), whose effects on coronary artery disease, stroke, and type 2 diabetes were assessed, again using MR. Moreover, we performed statistical colocalization and mediation analyses to increase the robustness of the findings. The integrative analysis identified seven plasma protein mediators, including collagen type VI alpha-3 (COL6A3). COL6A3 was strongly increased by BMI (β = 0.32, 95% CI: 0.26-0.38, P = 3.7 × 10(-8)) and increased the risk of coronary artery disease (odds ratio = 1.47, 95% CI:1.26-1.70, P =4.5 × 10(-7)) per s.d. increase in COL6A3 level. Further analyses found that a C-terminal fragment of COL6A3 known as “endotrophin” mediated the effect. 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 lower plasma levels of COL6A3-derived endotrophin and other protein mediators and reduce cardiometabolic risk, highlighting clinical translation of these findings. Conclusions: We provide actionable insights into how circulating proteins mediate the effect of obesity on cardiometabolic diseases using the integrative proteogenomic approach. Our study highlights the importance of body fat reduction to reduce the risk of cardiometabolic diseases and offers potential therapeutic targets, including COL6A3-derived endotrophin, which may be prioritized for drug development. Presentation: Thursday, June 15, 2023