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THU0456 Psoriatic Arthritis Locus Correlates with Cell-Specific Gene Expression
  1. A. Budu-Aggrey1,2,
  2. K. Steel2,
  3. D. Plant1,2,
  4. J. Bowes2,
  5. A. Barton1,2
  6. on behalf of the PAGE Consortium
  1. 1NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester Foundation Trust
  2. 2Arthritis Research UK Centre for Genetics and Genomics, The University of Manchester, Manchester, United Kingdom

Abstract

Background Psoriatic arthritis (PsA) is a complex genetic disorder that presents in up to one third of psoriasis patients. Due to the clinical overlap of PsA with both psoriasis and rheumatoid arthritis, treatment administered for PsA is often extrapolated from treatments developed for the other two diseases. The fact that a high proportion of PsA patients are non responsive to treatment, highlights the need for a novel therapeutic target to be identified. This can be achieved with the use of genetic and functional studies.

Objectives To identify and functionally characterise a novel susceptibility locus for Psoriatic Arthritis.

Methods Expression quantitative trait loci (eQTL) analysis of chromosome 5q31 was carried out. This region has been recently reported to be associated with PsA. Bioinformatic analysis was performed with the use of publically available databases, and data sourced from the encyclopaedia of DNA elements (ENCODE) project. The Illumina HumanHT12 v4 gene expression array was used to carry out cell specific eQTL analysis of the region, using CD8+ and CD4+ T lymphocytes obtained from 23 healthy individuals of known genotype.

Results Bioinformatic analysis of the 5q31 region identified potential eQTLs that influence the expression of P4HA2, SLC22A4 and SLC22A5. Evidence of cell specific effects was also found. Functional variants that could affect the regulatory role of the region were identified, including rs10065787 and rs708455. These SNPs lie within the transcription factor binding sites of basic leucine zipper transcription factor ATF-like (BATF), and runt-related transcription factor 3 (RUNX3). Both transcription factors are involved in CD8+ T cell differentiation, while a variant of RUNX3 has been found to be associated with PsA. When investigating specific cell types, the strongest eQTLs in the 5q31 region were found in CD8+ T lymphocytes. The strongest correlation was found with differential expression of SLC22A5 in CD8+ T lymphocytes (P =1.41x10-4), where the associated eQTL is in high linkage disequilibrium with disease SNPs in the region.

Conclusions The initial bioinformatic analysis carried out in the 5q31 region identified differentially expressed genes which could be potentially causal for PsA. Variants found to lie in RUNX3 and BAFT binding sites could provide a mechanism by which disease susceptibility arises. The eQTL analysis performed not only confirmed the differential expression of SLC22A5, but also highlighted the importance of CD8+ T lymphocytes in PsA. Further functional analysis will allow further characterisation of the 5q31 region and provide further insight of the mechanisms that contribute towards disease.

References

  1. Apel, M., Uebe, S., Bowes, J., Giardina, E., Korendowych, E., Juneblad, K. et al. (2013). Variants in RUNX3 Contribute to Susceptibility to Psoriatic Arthritis, Exhibiting Further Common Ground With Ankylosing Spondylitis. Arthritis & Rheumatism, 65, (5), 1224-1231.

  2. Kuroda, S., Yamazaki, M., Abe, M., Sakimura, K., Takayanagi, H., and Iwai, Y. (2011). Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression. Proceedings of the National Academy of Sciences, 108, (36), 14885-14889.

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.4407

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