title: Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis.
abstract: The ability to obtain gene expression profiles from human disease specimens provides an opportunity to identify relevant gene pathways, but is limited by the absence of data sets spanning a broad range of conditions. Here, we analyzed publicly available microarray data from 16 diverse skin conditions in order to gain insight into disease pathogenesis. Unsupervised hierarchical clustering separated samples by disease as well as common cellular and molecular pathways. Disease-specific signatures were leveraged to build a multi-disease classifier, which predicted the diagnosis of publicly and prospectively collected expression profiles with 93% accuracy. In one sample, the molecular classifier differed from the initial clinical diagnosis and correctly predicted the eventual diagnosis as the clinical presentation evolved. Finally, integration of IFN-regulated gene programs with the skin database revealed a significant inverse correlation between IFN-β and IFN-γ programs across all conditions. Our study provides an integrative approach to the study of gene signatures from multiple skin conditions, elucidating mechanisms of disease pathogenesis. In addition, these studies provide a framework for developing tools for personalized medicine toward the precise prediction, prevention, and treatment of disease on an individual level.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Inkeles
authors.affiliation: Division of Dermatology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Philip O
authors.initials: PO
authors.lastname: Scumpia
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lopez
authors.affiliation: Division of Dermatology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Rosane M B
authors.initials: RMB
authors.lastname: Teles
authors.affiliation: Crump Institute for Molecular Imaging, Institute for Molecular Medicine, Johnson Comprehensive Cancer Center, California NanoSystems Institute, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: Department of Dermatology, University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meller
authors.affiliation: Department of Dermatology, University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Ann Arbor VA Hospital, Ann Arbor, Michigan, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.affiliation: Department of Dermatology, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
authors.affiliation: Division of Dermatology, University of California, Los Angeles, Los Angeles, California, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA. Electronic address: rmodlin@mednet.ucla.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA. Electronic address: matteop@mcdb.ucla.edu.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
mesh_terms: D016000:Cluster Analysis; D006801:Humans; D016899:Interferon-beta / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D046228:Microarray Analysis; D008957:Models, Genetic; D011237:Predictive Value of Tests; D012871:Skin Diseases / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D059467:Transcriptome
chemical_list: D016899:Interferon-beta; D007371:Interferon-gamma
references.citation: Curr Opin Immunol. 2013 Feb;25(1):81-9
references.pmid: 23141566
references.citation: Blood. 2007 Jan 1;109(1):194-202
references.pmid: 16968902
references.citation: Science. 2013 Mar 22;339(6126):1448-53
references.pmid: 23449998
references.citation: PLoS One. 2012;7(3):e34594
references.pmid: 22479649
references.citation: Ernst Schering Res Found Workshop. 2006;(56):1-27
references.pmid: 16329644
references.citation: Nucleic Acids Res. 2009 Jan;37(1):1-13
references.pmid: 19033363
references.citation: BMC Bioinformatics. 2002 Jun 21;3:17
references.pmid: 12095422
references.citation: Biostatistics. 2010 Apr;11(2):242-53
references.pmid: 20097884
references.citation: Cell Mol Immunol. 2012 Jul;9(4):302-9
references.pmid: 22705915
references.citation: Clin Exp Immunol. 2013 Jun;172(3):507-12
references.pmid: 23600840
references.citation: J Allergy Clin Immunol. 2011 Apr;127(4):954-64.e1-4
references.pmid: 21388663
references.citation: PLoS One. 2012;7(1):e29161
references.pmid: 22235269
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):207-10
references.pmid: 11752295
references.citation: PLoS One. 2010 Mar 22;5(3):e9753
references.pmid: 20339534
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: BMC Genomics. 2013 Aug 01;14:527
references.pmid: 23915137
references.citation: Dermatology. 1992;184(4):265-70
references.pmid: 1482441
references.citation: Int J Clin Pract. 2006 Feb;60(2):201-11
references.pmid: 16451294
references.citation: Nat Med. 2008 Dec;14(12):1343-50
references.pmid: 19029983
references.citation: J Am Acad Dermatol. 1995 Jun;32(6):982-6
references.pmid: 7751469
references.citation: An Bras Dermatol. 2012 Nov-Dec;87(6):817-28; quiz 829-30
references.pmid: 23197199
references.citation: J Allergy Clin Immunol. 2008 Oct;122(4):689-693
references.pmid: 18774165
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14031-6
references.pmid: 12388780
references.citation: N Engl J Med. 2011 Jul 21;365(3):231-8
references.pmid: 21774711
references.citation: Clin Exp Dermatol. 2004 Nov;29(6):584-8
references.pmid: 15550127
references.citation: Br J Dermatol. 2010 Mar;162(3):568-78
references.pmid: 19818069
references.citation: J Invest Dermatol. 2014 Jul;134(7):1828-1838
references.pmid: 24441097
references.citation: PLoS One. 2008 Jul 16;3(7):e2737
references.pmid: 18648529
references.citation: J Allergy Clin Immunol. 2004 Nov;114(5):1209-15
references.pmid: 15536433
references.citation: Immunity. 2008 Jul 18;29(1):150-64
references.pmid: 18631455
references.citation: Science. 1991 Oct 11;254(5029):277-9
references.pmid: 1925582
references.citation: J Invest Dermatol. 2012 Nov;132(11):2552-64
references.pmid: 22763790
references.citation: J Invest Dermatol. 1995 Sep;105(3):407-10
references.pmid: 7665922
references.citation: Lancet. 1994 Jan 1;343(8888):25-6
references.pmid: 7905045
references.citation: J Invest Dermatol. 1997 Feb;108(2):200-4
references.pmid: 9008234
references.citation: J Clin Invest. 1994 Aug;94(2):870-6
references.pmid: 8040343