title: Integrative omics analysis of rheumatoid arthritis identifies non-obvious therapeutic targets.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Whitaker
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: David L
authors.initials: DL
authors.lastname: Boyle
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Bartok
authors.affiliation: Department of Orthopaedics, University of California San Diego School of Medicine, La Jolla, California, United States of America.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Ball
authors.affiliation: Department of Rheumatology, University Hospital Zürich, CH-8091, Zurich, Switzerland.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, United States of America; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D040901:Proteomics / Q000379:methods; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C465214:ELMO1 protein, human; C107953:RAC1 protein, human; D034741:RNA, Small Interfering; D020830:rac1 GTP-Binding Protein