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OP0295 Unique whole blood microrna biosignature for rheumatoid arthritis
  1. V Anaparti1,2,3,
  2. I Smolik1,3,
  3. X Meng1,2,3,
  4. N Mookherjee2,3,
  5. H El-Gabalawy1,2,3
  1. 1Rheumatic Diseases Unit
  2. 2Manitoba Center for Proteomics and Systems Biology
  3. 3Internal Medicine, University of Manitoba, Winnipeg, Canada

Abstract

Background RA susceptibility risk is disproportionately high (∼2–3fold) in Indigenous North American (INA) tribes compared to other populations1,2. Environmental, lifestyle & genetic factors account for <20% of observed disease variance suggesting contribution of additional risk determinants3. Emerging evidence suggests small non-coding microRNAs (miRs) e.g. miR-155, miR-146a, miR-26b are key contributors to RA pathogenesis4. In this project, we examined the role of miRs on RA incidence, and association with anti-citrullinated protein antibodies (ACPA), whose appearance precedes disease symptoms. We hypothesized that differential expression of specific miRs associated with disease symptoms will facilitate RA transition in genetically susceptible first-degree relatives (FDRs).

Methods Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from age-matched ACPA+ RA patients (n=18), non-symptomatic ACPA+ FDRs (n=12) and ACPA- healthy controls (n=12), who belonged exclusively to INA Cree-Ojibway communities of Northern Manitoba, Canada. Total RNA was isolated using miRVANA kit (Ambion). Expression of selected 32 miRs based on the published literature, and associated downstream mRNA targets, were monitored by quantitative real-time PCR, RNU48 and 18sRNA were used for input normalization for miRNA and mRNA expression respectively.

Results Whole blood expression profiling identified 10 differentially expressed miRs in RA patients compared to control subjects. Expression of miR-103a-3p was significantly up-regulated (∼2.3-fold; p=0.0062), whereas that of imiR-16, miR-24, miR-29a, miR-125a-3p, miR-203, miR-222, miR-223, miR-150 and miR-346 were down-regulated in RA patients compared to controls. Increased miR-103a-3p expression was also confirmed in PBMCs from ACPA+ RA patients (∼2 fold; p=0.0040) compared to controls. Further, miR-103a-3p expression was increased in ACPA+ FDRs (>4 fold) compared to controls (p=0.0005), and ACPA+ RA patients (p=0.0149). miR-103a-3p expression was consistently elevated in ACPA+ FDRs, when we analyzed samples obtained at two independent time points (1year apart). Consistent with this, expression of AGO1 and DAPK1 mRNA, downstream targets of miR-103a-3p, was decreased significantly (p<0.05) in ACPA+ FDRs compared to controls.

Conclusions This study defines a unique signature of dysregulated miRs amongst RA patients and their related FDRs within the INA cohort. Our results suggest a potential role of miR-103a-3p as a prognostic biomarker for pre-clinical RA.

References

  1. Barnabe et al J Rheumatol. 2008;35(6):1145–50.

  2. Smolik et al J Rheumatol. 2013;40(6):818–24.

  3. Viatte et al Nat Rev Rheumatol. 2013;9(3):141–53.

  4. Vicente et al Nat Rev Rheumatol. 2016 Apr;12(4):211–20.

References

Acknowledgements Canadian Institute of Health & Research (CIHR).

Research Manitoba

Disclosure of Interest None declared

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