Abstract 4147041: Genetic evidence implicating collagen type VI a3 in heart failure risk and aortic health

Background: Endotrophin, a peptide derived from the COL6A3 chain that is released during COL6 formation, has been associated with cardiorenal outcomes in human observational studies and has demonstrated a strong association with adverse outcomes in heart failure with preserved ejection fraction. Endotrophin may modulate various biologic processes, but its potential causal cardiovascular effects are at present poorly understood. Research Questions/Aims: We aimed to investigate the potential causal effects of COL6A3-derived endotrophin on cardiorenal outcomes in humans, and its mediating mechanisms. Methods: Using genetic summary data from the UK Biobank (Olink, N=51,637) and deCODE (SOMAScan, N=35,365) studies, we first validated genetic instruments for COL6A3-derived endotrophin. We then leveraged those genetic instruments to investigate the effects of endotrophin inhibition on primary cardiorenal outcomes, including coronary artery disease, abdominal aortic aneurysm (AAA), chronic kidney disease, and heart failure (HF). Results informed our secondary analyses, where we investigated the effects of endotrophin on pulse pressure and aortic diameter. Next, using independent genetic association summary statistics (N=200,000-1,000,000), we explored the human proteome to gain insights into mechanisms of action, and the human phenome to assess the widespread health implications of COL6A3-derived endotrophin. We adjusted for multiple comparisons using the false discovery rate method. Results: MR findings revealed a significant association between COL6A3-derived endotrophin inhibition and reduced risk of HF (OR=0.60; 95%CI=0.51, 0.77) and AAA (OR=0.49; 95%CI=0.31, 0.77). Proteome-wide MR suggested that genetically proxied COL6A3-derived endotrophin inhibition was significantly associated with reduced COL28A1 (β=-0.71; 95%CI= -0.88, -0.53) and MAM domain containing-2 (MAMDC2; β=-0.71; 95%CI=-0.84, -0.57) levels. Phenome-wide association MR analyses suggested that genetically proxied COL6A3-derived endotrophin inhibition was associated with reduced risk of thoracic aortic aneurysm (OR=0.35, 95%CI=0.21, 0.59) and bronchiectasis (OR=0.26, 95%CI=0.14, 0.48). Conclusions: This is the first study to validate genetic instruments for COL6A3-derived endotrophin, and to provide genetic evidence supporting a causal role for endotrophin on HF and AAA risk. Clinical trials are required to further explore the effect of pharmacologically perturbing COL6A3-derived endotrophin levels.