Genetic variants that sway protein restricting in immune cells can cause autoimmune disease

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• Source: Wellcome Sanger Institute


• Date: 17 Apr,2021

Certain genetic variants that cause modified protein binding in immune cells, are also seen in people at high risk of some autoimmune diseases, new research has found.

Researchers from the Wellcome Sanger Institute, Josep Carreras Leukaemia Research Institute in Spain, and the MRC London Institute of Medical Sciences (LMS) discovered that specific genetic variants, which alter the binding ability of a protein known as PU.1 in neutrophils, are also shown to be related to auto immune disease susceptibility.

This new study, published in Nature Communications (16 April 2021), builds on previous research named BLUEPRINT. BLUEPRINT revealed how variation in blood cells’ attributes and amounts can affect a person’s risk of developing complex diseases like heart disease, and autoimmune diseases including rheumatoid arthritis, asthma, coeliac disease and type 1 diabetes.

This new research has provided more mechanistic detail on how PU.1 and neutrophils are impacted by genetic variation and has provided researchers a list of candidate genes which would be of interest for further research to investigate if these have a causal influence on the development of autoimmune disease.

Differences in people, such as threat of disease, can be influenced by a number of factors. While some of this variation is affected by the environment and external factors such as diet, there is a substantial component driven by genetics. However, most variation isn’t driven through the operation of one gene but instead the amount of many subtle changes in regions or genes that control gene activity.

Previously, BLUPERINT ran large-scale genome-wide association studies (GWAS) to research which genetic differences are linked to changes in blood cells and when these have a link to disease. GWAS are powerful tools for identifying regions of the genome associated with individual variation and diseases. However, GWAS does not look at specific cell types, which makes it difficult to determine the genes that certain regions code for and the cell types they govern.

In this new study, scientists in the Wellcome Sanger Institute, Josep Carreras Leukaemia Research Institute, Spain, and the MRC London Institute of Medical Sciences (LMS), combined preceding GWAS data with in-depth functional analysis of neutrophils -a sort of immune cell that make up 80 percent of their white blood cells in the body.

They discovered that the genetic variants that are associated with an increased risk of autoimmune disease also have an effect on binding of a particular protein in neutrophils, called PU.1.

It is crucial to understand the mechanisms in the cell if we are to fully understand the impact of these on disease. In this case, how the genetic variants affect the ability of PU.1 binding, which goes on to modulate gene expression in neutrophils, could be vital in understanding the role that neutrophils play in certain autoimmune diseases.”

Dr Biola-Maria Javierre, Co-senior author and group leader, Josep Carreras Leukaemia Research Institute, Barcelona

While further research is needed to see if this change in the capability of PU.1 to bind directly triggers certain autoimmune diseases, this research provides further understanding about the impact of these genetic variants on the cells within the body. Along with this, the researchers suggest a list of candidate genes that could hold further information about the genetic causes of autoimmune disease.

Research such as this that integrates large-scale genetic research with functional analysis gives us essential data that widen our understanding of how differences in the human genome and epigenome interact to cause devastating common diseases. Building on this understanding through further research will help inform new avenues for treating these conditions.”

Stephen Watt, Lead author and senior staff scientist, Sanger Institute