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Project summary

There are now over 70 genetic loci associated with coronary artery disease (CAD), and over two-thirds of these are not associated with traditional CAD risk factors. Contribution of genetic variation to disease is complex, particularly for diseases such as CAD that develop over the lifetime of an individual. This may partially explain the apparent lack of association of these loci with CAD risk factors.

Understanding the mechanisms involved are important, especially for high-risk groups, eg, family members of individuals having an unexplained heart attack at a young age - we are uncovering how these gene loci confer risk. By integrating genomic and metabolomic data in over 1000 patients in the Framingham Heart Study (FHS), we previously investigated how CAD gene loci acting through unknown mechanisms confer their risk. For example, we discovered that the CAD gene ZC3HC1 is in fact associated with many lipid species, likely conferring its risk for CAD through this intermediate phenotype.

We are extending our exploration of CAD pathways using cryopreserved human myocardium from the Sydney Heart Bank via collaboration with Dr Sean Lal from the School of Medical Sciences at the University of Sydney. Excitingly, we have replicated findings made in our initial investigations in the FHS, and are now focusing on three novel pathways active in ischaemic heart disease. We will explore the underlying mechanisms in cellular and animal model systems to determine if these are viable therapeutic targets.