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A new study has used state-of-the-art single cell multiomic techniques to discover a novel population of immune cells that mediate a substantial proportion of the genetic risk of heart disease. The characteristics of these cells make them potential targets for new treatments.

Cardiovascular disease is the leading cause of death globally and is mainly caused by atherosclerosis—an inflammatory build-up of immune cells and fatty material in the walls of blood vessels. Atherosclerosis is influenced by cholesterol levels and there is a strong genetic component to the disease, but how genes convey this risk is largely unclear. The new study published in Circulation Research, the American Heart Association’s journal, used the latest single-cell techniques to examine how individual immune cells respond to oxidized-low density lipoprotein cholesterol—sometimes referred to as ‘bad’ cholesterol.

The team undertook a ‘multiomic’ approach to study the DNA and RNA in thousands of cells individually and this led to the discovery of a novel population of cells that they term ‘lipid-handling macrophages’. The researchers used information from diseased human arteries to construct a cellular atlas of atherosclerotic arteries and integrated this with the results of large-scale genome-wide studies of genetic risk for the disease. Lipid-handling macrophages were present in diseased arteries and mediate a high proportion of the genetic risk of the disease.

Macrophages are immune cells and in atherosclerotic arteries they swell up with fatty material and can then die releasing this material. The newly identified lipid-handling macrophages do not fill up with fatty material, but are very active in processing fatty molecules. A high proportion of the genetic influence on atherosclerotic heart disease is mediated through these cells indicating their importance in the disease process.

Taking this work further, the team identified the molecular mechanisms whereby certain specific genetic variants influence the response to bad cholesterol, such as variants in the FDX1 gene which acts on mitochondria, the power factories in cells. Understanding how genes operating in lipid-handling macrophages can alter disease risk offers new opportunities for treatment and prevention.

Chris O'Callaghan, senior author from NDM’s Centre for Human Genetics, said: 'Atherosclerosis causes heart disease, strokes and peripheral arterial disease which affects other organs. There is a huge need for new treatments and prevention. Although we know that there is genetic risk, understanding which cells this genetic risk is mediated through is essential to understand how best to design new therapies. The use of the latest technology and the latest analytical computational methods was essential to this study and the results demonstrate how valuable these approaches are in the discovery of new avenues for therapies.'

Read the full paper here: