%0 Journal Article
%A Yoshiji, Satoshi
%A Lu, Tianyuan
%A Butler-Laporte, Guillaume
%A Carrasco-Zanini-Sanchez, Julia
%A Su, Chen-Yang
%A Chen, Yiheng
%A Liang, Kevin
%A Willett, Julian Daniel Sunday
%A Wang, Shidong
%A Adra, Darin
%A Ilboudo, Yann
%A Sasako, Takayoshi
%A Koyama, Satoshi
%A Nakao, Tetsushi
%A Forgetta, Vincenzo
%A Farjoun, Yossi
%A Zeberg, Hugo
%A Zhou, Sirui
%A Marks-Hultström, Michael
%A Machiela, Mitchell J.
%A Kaalia, Rama
%A Dashti, Hesam
%A Claussnitzer, Melina
%A Flannick, Jason
%A Wareham, Nicholas J.
%A Mooser, Vincent
%A Timpson, Nicholas J.
%A Langenberg, Claudia
%A Richards, J. Brent
%+ Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Max Planck Society
%T Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease : 
%G eng
%U https://hdl.handle.net/21.11116/0000-0010-961B-7
%R 10.1038/s41588-024-02052-7
%7 2025-01-24
%D 2025
%* Review method: peer-reviewed
%X Obesity strongly increases the risk of cardiometabolic diseases, yet the <br>underlying mediators of this relationship are not fully understood. Given that <br>obesity strongly influences circulating protein levels, we investigated proteins <br>mediating the effects of obesity on coronary artery disease, stroke and type 2 <br>diabetes. By integrating two-step proteome-wide Mendelian randomization, <br>colocalization, epigenomics and single-cell RNA sequencing, we identified <br>five mediators and prioritized collagen type VI α3 (COL6A3). COL6A3 levels <br>were strongly increased by body mass index and increased coronary artery <br>disease risk. Notably, the carboxyl terminus product of COL6A3, endotrophin, <br>drove this effect. COL6A3 was highly expressed in disease-relevant cell types <br>and tissues. Finally, we found that body fat reduction could reduce plasma <br>levels of COL6A3-derived endotrophin, indicating a tractable way to modify <br>endotrophin levels. In summary, we provide actionable insights into how <br>circulating proteins mediate the effects of obesity on cardiometabolic <br>diseases and prioritize endotrophin as a potential therapeutic target.
%K Cardiovascular diseases, Drug discovery, Obesity, Personalized medicine

%J Nature Genetics
%V 57
%N 2
%& 345
%P 345 - 357
%I Nature America, Inc.
%C New York, NY
%@ 1061-4036