ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 2735

Integrative Analysis Of Multiple Omics Technologies Reveals a Novel Therapeutic Target For Rheumatoid Arthritis (RA)

David L. Boyle1, John Whitaker2, Beatrix Bartok3, Wei Wang4 and Gary S. Firestein5, 1Div of Rheum, UCSD School of Medicine, La Jolla, CA, 2Chemistry, UCSD School of Medicine, La Jolla, CA, 3Rheumatology, UCSD School of Medicine, La Jolla, CA, 4Chemistry, UCSD, La Jolla, CA, 5Div of Rheumatology, UCSD School of Medicine, La Jolla, CA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Epigenetics, Fibroblasts, rheumatoid arthritis (RA) and signal transduction

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Title: Genetics and Genomics of Rheumatic Disease II

Session Type: Abstract Submissions (ACR)

Background/Purpose:   Identifying novel therapeutic targets for immune-mediated disease has become increasingly challenging. We used an unbiased method to integrate multiple “omics” methodologies and evaluate the overlap between RA-associated genes identified in genome-wide association studies (GWAS), genes that are differentially expressed or genes that are differentially methylated in RA fibroblast-like synoviocytes (FLS). This analysis narrowed the search to a limited number of genes and allowed us to focus on Engulfment and Cell Motility Protein-1 (ELMO1), a gene not previously considered as a therapeutic target. We show how this novel candidate gene plays a key role in the pathogenic behavior of RA FLS.

Methods:   Data were from three types of genome-wide RA assays were integrated: (i) for sequence variation we used the NCBI GWAS database and extracted all gene that were mapped to SNPs that had been implicated in RA susceptibility (www.genome.gov/gwasstudies/); (ii) for gene expression we used public microarray datasets of RA, OA, and normal (NL) FLS (Gene Expression Omnibus Database); (iii) for DNA methylation we used a set of differentially methylated genes that we previously identified in RA, OA, and NL FLS (Genome Medicine 5:40 2013). For functional studies, passage 4 to 6 RA FLS were cultured in medium or PDGF and migration was measured using a scratch assay. Cell invasion was determined by measuring cell invasion into Matrigel-coated transwell plates. Rac1 activation was determined by measuring the Rac1-GTP bound form of Rac1 by Western blot. Gene knockdown was performed using the siRNA and Amaxa technology.   

Results:   The integrative analysis of the three unbiased genome-wide approaches identified 6 genes as different in RA compared to controls (OA and normal) in all datasets. Of the overlapping genes, we were particularly interested in the cytoplasmic engulfment protein, ELMO1, as it was differentially methylated in the promoter region, differentially expressed, and associated with RA due to an intron-6 polymorphism. This protein can bind to Rac1 in activated cells and potentially alter cell movement. We first confirmed that ELMO1 is expressed in RA FLS and synovium as determined by qPCR. siRNA knockdown was then performed, which decreased ELMO1 expression by >90% compared to control siRNA. ELMO1 deficiency decreased PDFG-induced FLS migration by 40% (p<0.02). In an invasion assay, ELMO1 siRNA markedly decreased invasion of PDGF stimulated RA FLS into Matrigel matrix compared with control siRNA. The mechanism ELMO1 function was determined by determining the effect of ELMO1 deficiency on Rac1 activation. These experiments showed that ELMO1 siRNA decreased peak PDGF-induced Rac1 activation by 80%.

Conclusion:   Integrative analysis of multiple unbiased genome-wide datasets is a novel method to identify potential therapeutic targets. One previously unanticipated target, ELMO1, emerged as a candidate gene in RA. ELMO1 plays a critical role as a regulator of FLS migration and matrix invasion by activating Rac1. These data show how one can use integrative studies to identify and validate novel therapeutic targets.


Disclosure:

D. L. Boyle,
None;

J. Whitaker,
None;

B. Bartok,
None;

W. Wang,
None;

G. S. Firestein,
None.

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/integrative-analysis-of-multiple-omics-technologies-reveals-a-novel-therapeutic-target-for-rheumatoid-arthritis-ra/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology