INTEGRATIVE PROTEOGENOMICS ANALYSIS IDENTIFIES COL6A3-DERIVED ENDOTROPHIN AS AN ACTIONABLE MEDIATOR OF THE EFFECT OF OBESITY ON CORONARY ARTERY DISEASE (VP066)

Friday, October 27, 2023

15:15 – 15:25 EST

First Author(s)

Satoshi Yoshiji

PhD candidate
McGill University/Broad Institute of MIT and Harvard
McGill University/Broad Institute of MIT and Harvard

Co-Author(s)

TL

Tianyuan Lu
GB

Guillaume Butler-Laporte
JC

Julia Carrasco-Zanini-Sanchez
YC

Yiheng Chen
KL

Kevin Liang
JW

Julian Willett
CS

Chen-Yang Su
SW

Shidong Wang
DA

Darin Adra
YI

Yann Ilboudo
TS

Takayoshi Sasako
VF

Vincenzo Forgetta
YF

Yossi Farjoun
HZ

Hugo Zeberg
SZ

Sirui Zhou
MH

Michael Hultstrom
NW

Nicholas Wareham
VM

Vincent Mooser
NT

Nicholas Timpson
CL

Claudia Langenberg

Corresponding Author(s)

JR

J. Brent Richards

Presenting Author(s)

Satoshi Yoshiji

PhD candidate
McGill University/Broad Institute of MIT and Harvard
McGill University/Broad Institute of MIT and Harvard

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. In this study, we aimed 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.

METHODS AND 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.

Conclusion: We provide actionable insights into how circulating proteins mediate the effect of obesity on cardiometabolic diseases using the integrative proteogenomic approach and offer novel therapeutic targets, including COL6A3-derived endotrophin, which may be prioritized for drug development.