Genetic and non-genetic determinants of clinical phenotypes in cardiomyopathy

Area of Science:

• Cardiology
• Genomics
• Molecular Biology

Background:

• Cardiomyopathy is a significant global health issue, characterized by diverse causes and presentations.
• Dilated cardiomyopathy (DCM) is frequently linked to titin truncating and lamin A/C mutations, which influence patient outcomes and treatment responses.
• Understanding the molecular underpinnings of DCM is crucial for advancing patient care.

Purpose of the Study:

• To explore the multi-omics landscape of dilated cardiomyopathy (DCM).
• To identify key genetic determinants and molecular signatures associated with DCM.
• To investigate the potential for omics-based patient stratification and precision medicine in cardiology.

Main Methods:

• Analysis of genomic, transcriptomic, epigenomic, proteomic, and metabolomic data from DCM patients.
• Integration of multi-omics datasets to uncover inter-omics associations.
• Comparison of molecular profiles between different DCM genotypes and healthy controls.

Main Results:

• Identified titin truncating mutations and lamin A/C mutations as major genomic drivers of DCM with distinct phenotypic consequences.
• Revealed transcriptomic and epigenomic alterations including DNA damage response activation, metabolic reprogramming, and dedifferentiation in DCM.
• Characterized proteomic and metabolomic signatures of the DCM heart and blood, highlighting fatty acid dependency, stress response, immune activation, and microbiota links.
• Demonstrated the utility of multi-omics data integration for patient stratification.

Conclusions:

• Multi-omics data integration provides a comprehensive understanding of DCM etiology and pathogenesis.
• Distinct molecular profiles associated with specific genotypes offer opportunities for personalized treatment strategies.
• Omics-based patient stratification holds promise for advancing precision medicine in cardiology for cardiomyopathy patients.