Does accelerated epigenetically defined ageing, including immune ageing, contribute to RA pathogenesis? Interaction in the development of RA

The group hypothesise that environmental factors such as smoking and genetic predisposition can cause premature ageing leading to an aged epigenome signature, driving immunesenescence and RA pathogenesis. DNA methylation at 350 specific sites, termed the epigenetic clock, has been identified as an indicator of biological age. The study will analyse existing data from patients with established RA and generate new data from very early RA cohorts across Europe to determine if the DNA methylation signature shows advanced ageing in RA patients and if this occurs in the earliest stages of the disease. Also immune phenotype at the various stages of disease development will be assessed to see if this occurs early or is a consequence of disease.

M1 (mth 1): Kick off workshop to organise sample collection, re-distribution to analysis sites, standard operating procedures for sample collection, storage and shipping.
M2 (mth 3): PRPgroup established and first meeting held to establish role and working method.
M3 (mth 12): Analysis of existing DNAm data complete and manuscript submitted. 2ndworkshop held.
M4 (mth 24): Collection of new samples & distribution to analysis sites complete. 3rdworkshop held.
M5 (mth 30): Immune phenotyping complete and manuscript prepared.
M6 (mth 36): DNAm analysis and modelling complete and manuscript prepared. Final workshop held.
M7 (mth 36): Public dissemination strategy finalised with PRP.Budget:

The interim data show that innate immunity is not significantly affected in very early RA, there is an increase in regulatory monocytes but this occurs only once the disease is diagnosed. However for adaptive immunity thymic atrophy, reduction in naïve T cells and the increases in memory T cells all occur very early in disease pathogenesis and are likely contributing to disease development rather than being a cause. Early analysis of DNA methylation in patients newly diagnosed with RA showed acceleration of biological age of between 2 and 5 years, with the higher value seen in male patients. Analysis of samples from early RA patients has been delayed due to the pandemic but is now underway.

• Sharma-Oates A, Zemedikun DT, Kumar K, Reynolds JA, Jain A, Raza K, Williams JA, Bravo L, Cardoso VR, Gkoutos G, Nirantharakumar K, Lord JM. Early onset of immune-mediated diseases in minority ethnic groups in the UK. BMC Med. 2022 Oct 13;20(1):346. doi: 10.1186/s12916-022-02544-5. PMID: 36224602; PMCID: PMC9558944.

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The project will include patient representatives at each site to support the writing of the patient information sheets and to help communicate the findings of the project. Close work with a patient group in Birmingham.