The role of clonal haematopoiesis in immune-mediated inflammatory diseases

This project aims to understand more about a what causes a group of diseases known as immune-mediated inflammatory disease, abbreviated as IMID. These include allergic conditions like asthma and eczema, autoimmune disorders such as rheumatoid arthritis, colitis and lupus and inflammatory conditions like psoriasis. All IMID are characterised by an overactive immune system causing damage to organs. Although much is known about these diseases, it is less clear why the immune system becomes activated in the first place. About half of the risk of developing an IMID is determined by inherited genetic factors that control immune responses. It is also known that diet, smoking and other environmental factors can contribute. We are interested in a third possibility, that DNA mutations occurring at random can increase the risk of developing an overactive immune system. All cells of the body have copies of our DNA that gradually mutate as we age. This is known as somatic mutation because it is seen only in the tissues of the body and does not get inherited through generations. Mostly these mutations are silent but a small proportion give cells a growth advantage that allows them to expand into a small clone with abnormal properties. We can see that the white blood cells that form the immune system develop these small clones in some people. It is possible that these blood-derived clones activate the immune system and contribute to inflammatory diseases. We are therefore looking in the DNA of people with IMID for evidence that they have an increase in clonal haematopoiesis (blood-derived clones) compared with people who do not have IMID. In the first part of the project we will examine a large cohort of patients with inflammatory bowel disease and healthy controls and look for evidence of that patients with disease have more clonal haematopoiesis in their DNA. In the second part of the project, we examine a smaller cohort of patients with rheumatoid arthritis who have been followed closely to see if they respond to treatment and if they remain well when treatment stops. In these cases, we can ask if the presence of clonal haematopoiesis is able to predict what will happen to them. Specifically, we want to find out if clonal haematopoiesis is an adverse factor that identifies patients who are less likely to respond to treatment or more likely to have a flare up once treatment is stopped. Both approaches will help us to define if clonal haematopoiesis contributes to IMID and inform ways to exploit this information in the future to improve personalised medicine and potentially develop new approaches to therapy.

Immune mediated inflammatory diseases (IMID) encompass a wide range of autoimmune, allergic and inflammatory disorders approaching 10% prevalence. Genome-wise association studies (GWAS) have identified risk alleles for many IMID. The remaining sporadic risk has been attributed to environmental factors but might also be accounted for by stochastic genetic events. Healthy tissues are known accumulate somatic mutations in genes that regulate cell activation, metabolism and proliferation leading to the development of measurable clonality. In the haematopoietic system, clonality may have systemic consequences and subtle changes in 'fitness' may drive the selection and enrichment of abnormal progeny, particularly under conditions of inflammation. The potential of clonal haematopoiesis to induce or amplify immune-mediated pathology has not been explored. In this proposal we measure CH in a large cohort of IBD cases and age-matched controls drawn from the NIHR IBD BioResource to determine if CH is more prevalent in IBD than in controls. We also examine cohorts of RA patients participating in observational trajectory studies to determine whether CH is more prevalent a) in treatment-naïve patients who fail to achieve an adequate response; b) in stable patients with a short drug-free remission after treatment cessation. Together these studies will determine the prevalence of CH in two distinct IMID cohorts with different age distribution and immunopathology. The data will reveal any potential prognostic value in the measurement of CH and provide impetus to examine CH in population-based DNA collections with prospective health reporting, such as the UK Biobank.

The main impacts of the study are:
1) to define the prevalence of clonal haematopoiesis in IBD and RA, relative to controls
2) to investigate associations of clonal haematopoiesis with prognosis in RA
3) to assess the potential importance of clonal haematopoiesis as a common mechanism involving a wide range of IMID.

Academic beneficiaries
These include multiple clinical disciplines involved in the care of patients with IMID including gastroenterologists, rheumatologists, dermatologists, and immunologists. The proposal links the process of somatic mutation, traditionally only associated with cancer biology, to dysregulation of immunity. It fosters a new vision of the life history of somatic genomes in which mutational trajectories influence pathology in multiple different ways, beyond the domain of neoplasia. The research is likely to open a new avenue of investigation utilising population-based DNA cohorts with prospective capture of health data, such as the UK Biobank. The ultimate goal will be to pre-empt the onset of disease in healthy individuals and provide opportunities for preventative management. The research will build capacity and skills in centres of academic excellence and foster new cross-disciplinary collaborations.

Technology and commercialisation
The research will have a broad impact in technologies extending from academic beneficiaries of the basic research. Somatic mutation is a novel aspect of the pathology of IMID and may be exploited for stratification, prognostication and personalised therapeutics. This may lead to new clinical technologies based on genome analysis to better understand response or resistance to therapy, define molecular targets at individual level and potentially identify healthy persons at risk of disease. Intellectual property that has translational potential will be protected and exploited to drive commercialisation to maximise health and economic benefits.

The NHS and wider public
Translation of the research into more effective stratification, treatment and even prevention of disease will have wide impact on many patient groups at a national and international level. IMID are increasing in prevalence in the developed world incurring significant morbidity, early mortality and great demand on healthcare resources. Progress in understanding pathogenesis leading to clinical advances will have substantial socio-economic benefits to individuals and healthcare systems.