Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets

PLoS One. 2015 Apr 22;10(4):e0124254. doi: 10.1371/journal.pone.0124254. eCollection 2015.

Abstract

Identifying novel therapeutic targets for the treatment of disease is challenging. To this end, we developed a genome-wide approach of candidate gene prioritization. We independently collocated sets of genes that were implicated in rheumatoid arthritis (RA) pathogenicity through three genome-wide assays: (i) genome-wide association studies (GWAS), (ii) differentially expression in RA fibroblast-like synoviocytes (FLS), and (iii) differentially methylation in RA FLS. Integrated analysis of these complementary data sets identified a significant enrichment of multi-evidence genes (MEGs) within pathways relating to RA pathogenicity. One MEG is Engulfment and Cell Motility Protein-1 (ELMO1), a gene not previously considered as a therapeutic target in RA FLS. We demonstrated in RA FLS that ELMO1 is: (i) expressed, (ii) promotes cell migration and invasion, and (iii) regulates Rac1 activity. Thus, we created links between ELMO1 and RA pathogenicity, which in turn validates ELMO1 as a potential RA therapeutic target. This study illustrated the power of MEG-based approaches for therapeutic target identification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology
  • Cell Movement
  • Cell Proliferation
  • DNA Methylation
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • Humans
  • Proteomics / methods
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology
  • rac1 GTP-Binding Protein / genetics*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • ELMO1 protein, human
  • RAC1 protein, human
  • RNA, Small Interfering
  • rac1 GTP-Binding Protein

Grants and funding

This project was supported by a grant from the Research Foundation (GSF).