The genetic drivers of complex diseases such as inflammatory bowel disease (IBD) have been uncovered by scientists from Wellcome Sanger Institute.
They stimulated macrophages – a type of white blood cell – with biological factors that mimic infection in one of the largest studies of its kind.
Macrophages attack and destroy pathogens cells by phagocytosis. Picture: iStock
The findings provide insights into how our genes influence the risk of developing common diseases and have enabled the creation of MacroMap, a large dataset that maps genetic effects in immune cells.
The work will enable future studies exploring genes in certain disease contexts to be more realistic.
Dr Carl Anderson, senior author at the Wellcome Sanger Institute, said: “By uncovering how our genes behave during more realistic immune response scenarios, our research brings us closer to understanding the genetics behind why some people are more vulnerable to certain diseases. We hope our research will help enable more effective prevention and treatment of diseases in the future.”
Changes in DNA associated with disease are believed to influence the extent to which certain genes are turned on or off, but these changes are often missing from existing databases.
That is because studies typically use ‘resting’ cells, which means they have not been activated by stimuli such as bacterial or viral infections, meaning they are not giving the full picture of gene activity when cells are activated during a normal immune response.
Dr Nikolaos Panousis, co-first author, formerly at the Wellcome Sanger Institute, said: “In this study, we aimed to take a more realistic approach to studying autoimmune conditions by using different stimuli to mimic what naturally occurs in disease-relevant contexts.
“For example, when you have an infection, a specific pathway is triggered, so we stimulated the cells to replicate that response. We hope our study will serve as a stepping stone towards providing a more comprehensive picture of the cellular and molecular processes during disease and how genetic differences between people influence these processes.”
The Sanger Institute researchers sought to understand how genetic differences between people affect the behaviour of a type of immune cell called a macrophage when stimulated to different conditions and stressors. Macrophages – a form of white blood cell – engulf and digest harmful substances or cellular debris.
They used human induced pluripotent stem cells (iPSCs) – cells taken from adult tissue that can be programmed to become many different cell types – from 209 healthy people and turned them into macrophages.
Then they activated the macrophages with 24 different stimuli that trigger an immune response to mimic infections and inflammation. The stimuli include components such as viral mimics, bacterial elements and immune signalling molecules.
RNA was collected from the cells six and 24 hours after stimulation to measure gene expression, to see which genes were turned on or off in response to each stimulus.
The resulting MacroMap revealed many links between genes and diseases that were only visible after stimulation. The researchers identified 1,955 instances where gene activity overlapped with genetic variants associated with disease and 51 per cent would have been missed using unstimulated cells.
A genetic variant associated with coronary artery disease, for example, was found to increase the activity of a gene called CTSA, but only when macrophages were stimulated with inflammatory signals.
The researchers studied the genetic drivers of disease. Picture: iStock
A complementary study that is also part of the MacroMap project explored RNA splicing. In this process, cells cut and rearrange RNA – the instructions from DNA to make proteins.
The aim was to understand how genes were spliced under the same 24 stimuli and how people’s genetic differences influenced splicing patterns.
More than 5,000 genes changed their splicing patterns when macrophages were activated by stimuli, they found.
Genetic risk factors for autoimmune diseases were linked to differences in splicing.
For example, one genetic change was found to increase the use of a rare version of a gene called PTPN2, which normally helps control inflammation. This change may increase the risk of developing IBD.
Dr Omar El Garwany, co-first author at the Wellcome Sanger Institute, said: “Our project, MacroMap, provides a valuable reference point as it’s a rich dataset that researchers can use to explore genetic mechanisms behind a wide range of diseases. MacroMap extends beyond autoimmune diseases, as immune cells such as macrophages are found throughout the body, so we hope we and many other researchers can use MacroMap for studying other diseases.
“Additionally, by studying alternative splicing, MacroMap not only investigates which genes are turned on/off but also which versions of genes are expressed. We trust that our study shows that the macrophage response changes gene expression both quantitatively and qualitatively.”
The studies, published in Nature Communications, underscore the importance of studying genes in the right biological context. Future studies could increasingly focus on dynamic or stimulated cells to uncover the full picture of how genes influence health and disease.
The work may also inform treatment research such as RNA therapeutics, which offer a novel approach to targeting hard-to-treat diseases.