MultiomIcs based Risk stratification of Atherosclerotic CardiovascuLar disEase

Project Information

MIRACLE

Grant agreement ID: 101115381

DOI

10.3030/101115381

EC signature date 14 June 2023

Start date 1 October 2023

End date 30 September 2027

Funded under

• The European Innovation Council (EIC)

Total cost

€ 4 599 866,25

EU contribution

€ 4 599 866,25

Coordinated by

ITA-SUOMEN YLIOPISTO
Finland

Periodic Reporting for period 1 - MIRACLE (MultiomIcs based Risk stratification of Atherosclerotic CardiovascuLar disEase)

Reporting period: 2023-10-01 to 2024-09-30

Summary of the context and overall objectives of the project

Atherosclerotic cardiovascular diseases (ASCVDs) are the leading causes of death globally, often striking without warning. Traditional risk prediction models, which rely on factors like age, cholesterol levels, and smoking habits, fail to account for genetic influences and lifelong exposure to various risk factors. The MIRACLE project seeks to fill this gap through advanced genetic and molecular research aimed at developing more accurate prediction tools.

The project focuses on understanding genetic variations associated with heart disease, stroke, and other cardiovascular conditions by analyzing extensive genetic datasets. It also aims to identify patient subtype and sex-specific patterns in how these diseases manifest, utilizing patient-derived blood and tissue samples. Additionally, MIRACLE is working on integrating genetic data with other biological information to develop enhanced risk scores and predictive tools that use biomarkers to better identify individuals at high risk of cardiovascular events.

The overarching goal of the MIRACLE project is to revolutionize the prediction of ASCVD, facilitating earlier interventions and more personalized treatments. This not only promises to improve individual patient outcomes but also aims to reduce the broader economic burden on healthcare systems. The project's outcomes are expected to influence future health policies and transform how at-risk patients are diagnosed and managed.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Work Package 1 (WP1) of our project delved into the genetic foundations of major atherosclerotic cardiovascular diseases (ASCVD) such as Coronary Artery Disease (CAD), Peripheral Arterial Disease (PAD), and Ischemic Stroke (IS). Our analysis indicated that CAD and PAD have more genetic similarities with each other compared to IS. We identified 233 genetic regions linked to increased risk and pinpointed 17 potential new drug targets, including HTRA1, aimed at preventing and treating atherosclerosis. Notably, the integration of polygenic risk scores (PRS) with traditional clinical assessments led to a 10% improvement in the accurate classification of patients into higher risk categories.

In WP2, we expanded our study to include 1125 patients to analyze the gene activity in atherosclerotic plaques. We discovered five distinct plaque types, some of which show variations between men and women, highlighting the need for personalized treatment approaches. This part of the research also identified new biomarkers that could assist in detecting plaques that are more likely to lead to complications, thus improving predictions of future ASCVD risks.

In WP3, we discovered that genomic regions linked to increased ASCVD risk often harbor multiple causal genetic variants, enhancing our understanding of their function and role in disease progression. This data will feed into novel PRS models in upcoming phases of the project. We also developed CADnets, an innovative approach that merges individual cell data with gene regulatory networks from tissues of 600 patients, effectively identifying crucial arterial networks linked to the severity of ASCVD.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Results Beyond the State of the Art:
• The MIRACLE project has made key breakthroughs in understanding ASCVD by identifying 233 genetic regions linked to different disease subtypes. Identification of potential novel drug targets among these regions, offers new avenues for the development and repurposing of therapies aimed at ASCVD prevention and treatment.
• We achieved proof of concept for innovations in risk prediction by integrating PRS with clinical data, which improved patient classification into higher-risk categories by 10%.
• Transcriptomic analysis has uncovered five distinct plaque subtypes, enriching personalized medicine approaches and diagnostic accuracy by identifying sex-specific variations.
• A pivotal component of the project is the development of a web portal intended to facilitate the sharing of data on thousands of human plaque samples. This resource is expected to be a vital tool for the global research community, promoting collaborative efforts and pushing the boundaries of scientific discovery in cardiovascular health.

Potential Impact and Future Directions:
• The project’s contributions are set to transform healthcare by reducing unnecessary medical procedures and optimizing therapeutic approaches, thus improving patient outcomes and curtailing healthcare costs.
• The commercial potential of the newly identified biomarkers and drug targets is substantial, particularly in fostering the growth of personalized diagnostics and therapies.
• To translate these scientific achievements into practical applications, further research and validation through larger clinical trials are imperative. The findings are expected to influence future medical guidelines and standards for disease management, necessitating close cooperation with major societies and integration into clinical practice.
• For maximum impact, continued interdisciplinary collaboration, alongside supportive measures for commercialization, regulatory compliance, and standardization, will be essential. Additionally, securing access to financial resources and international partnerships will be crucial in transitioning these scientific discoveries to broad clinical implementation.

MIRACLE consortium members in Helsinki in November 2023