Topology of biological networks yields insight into protective role of diabetes in the development of aneurysm

There is a huge amount of available biological data for different organisms, describing interactions between biological macromolecules. Network representations of such interaction data enable graph theoretic approaches to identify topological properties of these networks which are different from what is expected at random. This is how we can, for example, reveal the connection between a specific topological property of a node in a biological network and a specific biological function or a process. In this presentation I will talk about an application of graph theory to human biological networks in research of cardiovascular diseases.

Cardiovascular diseases (CVD) are common in people with diabetes. However, several recent clinical studies suggested a protective role of diabetes in the development of one of the common CVDs - aneurysm. I will present our published work where we use topology of biological networks to explore this interesting relationship between diabetes and aneurysm. We also explain why there is no similar influence of diabetes on atherosclerosis, given that aneurysm and atherosclerosis are CVDs with similar risk factors. Motivated by the significance of genetic interactions in understanding disease–disease associations, we integrate genetic interaction data and protein-protein interaction network to create a subnetwork of pathways related to the three diseases. We then use a ‘‘brokerage’’ measure - a topological measure that describes importance of a node in the network for the interconnectedness of its neighbourhood. We use this measure to find set of ‘‘broker‘‘ proteins that are able to disrupt the pathways that they are part of. We suspect that a mutation of a gene in a pathway involved in diabetes is related to a functional change of a protein in an aneurysm-related pathway. Hence, among broker proteins, we identify 16 that are involved in an aneurysm or an atherosclerosis pathway and are encoded by genes participating in genetic interactions with a gene in a diabetes pathway. Interestingly, this set is enriched in kinases which can act like protein switches turning them on or off, explaining how functional changes of such proteins could result in the disruption of pathways. We also find that several of the kinases among broker genes, that are both on aneurysm and atherosclerosis pathways, are pleiotropic. It is known that mutations of pleiotropic genes could have effects only on one of the traits, which explains why pleiotropic kinases that are involved in both aneurysm and atherosclerosis pathways could disrupt aneurysm pathways explaining the reduced risk of aneurysm in diabetes patients, but not affect the atherosclerosis pathways.