THE MAIN OBJECTIVES OF THE PROJECT:
The DISCORD project investigates individuals with similar CV risk but discordant atherosclerosis and arterial stiffness burdens, using a multi-omics approach. It aims to elucidate pathophysiological mechanisms of vascular resilience and susceptibility, enhance cardiovascular disease risk prediction and prevention, and uncover potential therapeutic targets.
RESEARCH HYPOTHESES:
H1.General Drivers of Atherosclerosis and Arterial Stiffness:
Donors with matched cardiovascular risk but pronounced risk-burden discordance (Group A vs. B) show distinct omics profiles revealing shared disease drivers.
H2.Specific Drivers and Protectors:
1) In low-risk donors with pronounced risk-burden discordance (Group 1 vs. 2), omics profiles identify driving mechanisms.
2) In high-risk donors with pronounced risk-burden discordance (Group 3 vs. 4), omics profiles identify protective mechanisms.
H3.Pathways and Mechanisms:
Multi-omics signatures reveal biological pathways underlying arterial stiffening, clarifying mechanisms beyond traditional risk factors.
H4.Leveraging Known Variants and PRS
Known gain- and loss-of-function variants (e.g., PCSK9, APOC3, MMP9) and polygenic risk scores (PRS) explain risk-burden discordance in atherosclerosis and arterial stiffness beyond traditional factors.
H5.Territory Specificity:
Omics alterations, differing across vascular beds (CAD vs. PAD), reflect location-specific disease mechanisms.
H6.Clinical Prediction:
Omics signatures explaining discordance predict adverse cardiovascular outcomes, improving risk stratification.
DISCORD uses UKBB, EstBB, and a specialized cohort of 400+ deeply phenotyped PAD patients (including multi-omics, inflammatory markers, and vascular function measures) to analyze molecular and phenotypic associations with vascular changes across four WPs: subclinical arterial stiffness, coronary plaque burden, clinical CAD and PAD, and PAD deep phenotyping.