Small RNAs and risk of rheumatoid arthritis

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Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease affecting nearly 1% of Veterans. Early and aggressive treatment of RA improves likelihood of remission and reduces disability. Therefore, biomarkers identifying patients with high likelihood of developing disease could stratify individuals who would benefit from early interventions aimed at preventing disease and reducing disability. Such biomarkers may also provide insight into disease mechanisms. Our overarching goal is to determine the role of human and microbial sRNAs in the development of RA. The rationale for the proposed research is that sRNAs are powerful gene regulators and markers of disease. We have found that circulating human and microbial sRNAs are altered in established RA patients compared to control subjects, are associated with disease measures and can alter inflammatory cellular pathways. Building on preliminary data, we will define circulating human (Aim 1) and microbial (Aim 2) sRNAs that predict development of RA and change between preclinical and clinical RA in discovery and validation cohorts and identify the function of predictive sRNAs. Aim 3 will determine if microbiome alterations in new-onset untreated RA are reflected in alterations in plasma microbial sRNAs. The proposed research is significant because it will help us to identify patients with high likelihood of developing RA, enabling us to identify individuals who would benefit from early interventions aimed at preventing disease and reducing disability. The proposal is innovative because it has the potential to revolutionize our understanding of markers and mechanisms underlying development of RA and our understanding of how the human microbiota can influence immune function. The study is high impact because it could identify fundamental, targetable mechanisms underlying developing RA and could lead to targeted sRNA therapeutics.