• Queen Mary University of London
  • Barts Health NHS
  • Bradford NHS
  • Manchester Uni

S00003: Functional follow-up of immune gene knockouts

Lay summary: Functional follow-up of immune gene knockouts

Please provide information on the aims of the proposed research including the research question(s) that you are aiming to answer and the health condition(s) under investigation.

The immune system is responsible for defending the body from infections. Problems with the immune system are associated with several important diseases, including allergies, autoimmunity, serious infections, and cancer. Despite the fact that there are many studies linking differences in people’s genes with these conditions, the actual genes that are involved and how they work are poorly understood. As an example, increased resistance or susceptibility to bacterial and viral infections have been linked to differences in genes. Genes contain the code for producing different proteins in the body. Changes in this genetic code can affect the amount of protein that is produced or the way in which the protein functions. This study aims to identify the role of gene products (proteins) in immune responses by analysing what kinds of immune cells are present in the blood of individuals with rare genetic variants (changes in their genetic code), and how these cells are functioning. We will also analyse the medical history of these individuals as this will give us insight into their immune system's ability to fight infection. Because of the way that the Genes & Health project was designed, it provides a unique opportunity to gain insight into how immune genes work. For this study, we are focusing on genes that have been previously linked to host defence against viruses such as hepatitis, to the development or activation of particular types of immune cells, to autoimmune diseases, in which the body’s immune system goes into over-drive and attacks its own cells (e.g. type I diabetes, psoriasis, inflammatory bowel disease), and to asthma and allergies. These data will be used to inform the scientific and medical community and potentially contribute to the improvements in the prevention and treatment of infections and immune disorders.

How will your research improve health in East London?

This research aims to lead to a better understanding of how these genes work in the immune system. This may ultimately lead to new therapies to help fight infections or autoimmune diseases, but we stress that this is a basic research study. We will also obtain information about the normal functioning of blood cells in British Pakistani and British Bangladeshi people, which should allow these populations to be integrated into broader health research on immunity and infection, and we expect that this will ultimately lead to new treatments for diseases like hepatitis. In the shorter term, our findings may suggest that people with changes in these genes are particularly susceptible to certain types of infections, which will be informative to the medical and research communities.

How does your research meet the other purposes of ELGH?

Our health research study will use the data collected in Stage 1 of ELGH to advance current knowledge on the correlation between variation in DNA sequences and the function of immune cells, which are essential for human health. This information will be linked to health records to help us understand better the factors that determine susceptibility to infections or autoimmune diseases. These goals are in line with ELGH’s aims, including the support and enabling of further health research studies in East London. Because this will be one of the first research studies to use the ELGH cohort, it will also be valuable in demonstrating the utility of ELGH for biomedical research.

Please give a non-technical description of how the research will be undertaken.

We have already identified a set of genes that we believe, based on previous research, to be involved in the immune system. The study will begin with the identification of Stage 1 ELGH participants who have rare genetic variants in one of these genes, where the variant is likely to change how much protein is being produced. Based on this information, some individuals will be selected and invited to participate in the study by a member of the research team. We will also invite some people who do not have genetic variants in the genes of interest, so that we can compare results between people with and without the gene variants. The invitation to take part in this study will include a participant information sheet with detailed information on the study. Volunteers can then express their interest in participating in the study either by phone, email or by returning a freepost reply slip. At this point, volunteers are also given the opportunity to ask further questions about the study and they will give informed consent by signing a consent form. Volunteers that agree to take part in this study will be invited to donate up to 50mls of blood (about 4 tablespoons) and this sample will be used to study how genetic variation has affected the development and distribution of their immune cells in the blood. We will also investigate the functional potential of these immune cells by testing their ability to respond to stimuli that mimic bacterial and viral infections. From this preliminary data we might require further tests from some participants, who may be invited to donate further blood samples on a few further occasions per year. Volunteers will be able to cease participation at any time. In parallel with these laboratory investigations, we will study using anonymised health records whether a volunteer's genetic variation is related to their ability to fight infections or susceptibility to immune disorders.

Please state the approximate number of volunteers to be included (i.e. whether the full cohort or a subset).

In the first instance, we wish to recall approximately 50 people (including about 38 people with variants in these immune-related genes, and 12 randomly sampled matching controls who do not have variants in these genes). We will obtain electronic health record (EHR) data from these people, as well as aggregate EHR data from all ELGH participants for comparison. When more ELGH data become available, we may want to recall additional people with the same or other variants in immune-related genes.


Lead Investigators

Dr Richard Durbin, Wellcome Trust Sanger Institute

Dr Dan Pennington Blizard Institute, Queen Mary University, London

Co-applicants and collaborator details

Dr Hilary Martin, Wellcome Trust Sanger Institute

Dr Monica Escorcio-Correia Blizard Institute, Queen Mary University, London

Dr Gosia Trynka Wellcome Trust Sanger Institute

Prof Aine McKnight Blizard Institute, Queen Mary University, London

Prof Angus Lamond School of Life Sciences, University of Dundee