Detection of somatic mutations in rheumatoid arthritis

Fareeha Tariq 

The project takes a novel approach at the interface of a long-term condition (RA) and ageing.

The Study

Rheumatoid arthritis (RA) is an autoimmune disease most commonly diagnosed in aging population. The exact cause of RA is still unknown; however, extensive medical research has revealed that dysregulation of immune cells (mainly B cells and T cells) is responsible for the inflammation in joints. In our study, we are hypothesizing that somatic mutations in blood cells are responsible for clonal haematopoiesis of indeterminate potential (CHIP), which leads to the subsequent failure of self-tolerance of the immune system and onset of autoimmunity in RA.

Clonal haematopoiesis of indeterminate potential (CHIP) is defined as the presence of expanded blood-cell clones carrying somatic mutations associated with hematologic cancers. Individuals with CHIP are not affected with hematologic malignancies, however, they are at increased risk of developing such malignancies. The incidence of CHIP increases with age. Studies have established a link between CHIP and onset of age-associated Cancers and Cardiovascular diseases. The idea of CHIP and somatic mutations in RA is still unproven, however, it is gaining momentum. Most recent studies have reported the presence of somatic mutations in immune-related genes and clonal expansion of CD8+ T cells in untreated RA patients. These findings give us motivation and hope to investigate if CHIP-associated somatic mutations are the underlying cause of the pathogenesis of RA.

As part of this study, we are focusing on two RA patient cohorts. One cohort consist of patients who have been treated with disease modifying anti-rheumatic drugs (DMARD) and their disease is under drug-free remission. However, some of these patients have relapsed post drug cessation. The second cohort consists of refractory patients. These patients have been treated with DMARDS and biologic drugs but they do not respond to any attempted form of treatments. The experimental procedure involves extracting DNA and RNA from the blood cells of these patients. The DNA will be sequenced initially to identify regions consist of CHIP-associated somatic mutations. These regions will then be looked at further using RNA sequencing to elucidate if somatic mutations have an effect on the function of proteins which may predict the severity of RA and its response to therapy.

Project milestones

• To perform a pilot experiment, detecting the prevalence of clonal haematopoiesis driver mutations in different RA cohorts, using targeted sequencing
• To perform a larger experiment, with large sample size and a new RA cohort (early RA).
• To perform exome on two RA cohorts
• To test whether immunophenotype, clone size or somatic mutation predict the severity of RA and its response to therapy.