Understanding why some gene changes raise the risk of developing heart disease

Molecular mechanism linking chr9p21 genetic risk variants to cardiovascular disease: Altered IL-1/TLR signalling and transcriptional regulation of IRAK4

Over the past two decades a wealth of research evidence – including from BHF-funded studies - has revealed a great deal about the importance of genetics underlying coronary heart disease. It has shown that changes in many different genes can raise our risk of heart disease, but – in most cases – we still don’t know why. BHF Professor Ziad Mallat is investigating how a particular change in the gene chr9p21 makes people more susceptible to coronary heart disease. He has discovered that vascular smooth muscle cells (which are a component of blood vessels) with this change in chr9p21 are more sensitive to inflammation. This is because they have higher activity in a gene called IRAK4, which is important in making inflammation happen. Professor Mallat thinks that this might explain the link between the change in chr9p21 and the coronary arteries becoming inflamed and contributing to heart disease. In this project he will try to understand exactly how the chr9p21 gene variations increase IRAK4 activity. This work could identify important pathways that can specifically be targeted by drugs to reduce the risk of heart disease in people with this change in the chr9p21 gene.