title: Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets.
abstract: Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state.
  
  
  
  We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy.
  
  
  
  Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets.
  
  
  
  We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address a major gap in knowledge regarding the systemic changes underlying skin-specific manifestation of vitiligo. Several transcriptional "hot spots" observed in both environments offer prioritized targets for identifying disease risk genes. Finally, within the transcriptional framework of VL, we identify five novel molecules (STAT1, PRKCD, PTPN6, MYC and FGFR2) that lend themselves to being targeted by drugs for future potential VL-therapy.
authors.affiliation: Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 6078 Clinical and Translational Research Center, 875 Ellicott Street, Buffalo, NY, 14203, USA.
authors.forename: Rama
authors.identifier: 0000-0003-3642-8255
authors.initials: R
authors.lastname: Dey-Rao
authors.affiliation: Department of Dermatology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 6078 Clinical and Translational Research Center, 875 Ellicott Street, Buffalo, NY, 14203, USA. aasinha@buffalo.edu.
authors.forename: Animesh A
authors.initials: AA
authors.lastname: Sinha
mesh_terms: D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000235:genetics; D015415:Biomarkers; D016022:Case-Control Studies; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D058990:Molecular Targeted Therapy; D015398:Signal Transduction; D059467:Transcriptome; D014820:Vitiligo / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*
chemical_list: D015415:Biomarkers
keywords: Autoimmune; Interactome; Microarray; Peripheral blood; Type I and II Interferon; Vitiligo