title: Multiple Transcriptome Data Analysis Reveals Biologically Relevant Atopic Dermatitis Signature Genes and Pathways.
abstract: Several studies have identified genes that are differentially expressed in atopic dermatitis (AD) compared to normal skin. However, there is also considerable variation in the list of differentially expressed genes (DEGs) reported by different groups and the exact cause of AD is still not fully understood. Using a rank-based approach, we analyzed gene expression data from five different microarray studies, comprising a total of 127 samples and more than 250,000 transcripts. A total of 89 AD gene expression signatures '89ADGES', including FLG gene, were identified to show dysregulation consistently across these studies. Using a Support Vector Machine, we showed that the '89ADGES' discriminates AD from normal skin with 98% predictive accuracy. Functional annotation of these genes implicated their roles in immune responses (e.g., betadefensin, microseminoprotein), keratinocyte differentiation/epidermal development (e.g., FLG, CORIN, AQP, LOR, KRT16), inflammation (e.g., IL37, IL27RA, CCL18) and lipid metabolism (e.g., AKR1B10, FAD7, FAR2). Subsequently, we validated a subset of signature genes using quantitative PCR in a mouse model. Using a bioinformatic approach, we identified keratinocyte pathway over-represented (P = <0.0006) among the 89 signature genes. Keratinocytes are known to play a major role in barrier function due to their location in the epidermis. Our result suggests that besides immune- mediated pathway, skin barrier pathways such as the keratinocyte differentiation pathway play a key role in AD pathogenesis. A better understanding of the role of keratinocytes in AD will be important for developing novel "barrier therapy" for this disease.
authors.affiliation: Division of Immunology, Allergy & Rheumatology, Department of Internal Medicine, University of Cincinnati, Cincinnati, United States of America.
authors.forename: Debajyoti
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States of America.
authors.forename: Lili
authors.initials: L
authors.lastname: Ding
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States of America.
authors.forename: Umasundari
authors.initials: U
authors.lastname: Sivaprasad
authors.affiliation: Division of Immunology, Allergy & Rheumatology, Department of Internal Medicine, University of Cincinnati, Cincinnati, United States of America.
authors.forename: Esmond
authors.initials: E
authors.lastname: Geh
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States of America.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Biagini Myers
authors.affiliation: Division of Immunology, Allergy & Rheumatology, Department of Internal Medicine, University of Cincinnati, Cincinnati, United States of America.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States of America.
authors.forename: Gurjit K
authors.initials: GK
authors.lastname: Khurana Hershey
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, United States of America.
authors.forename: Tesfaye B
authors.initials: TB
authors.lastname: Mersha
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000378:metabolism; D016002:Discriminant Analysis; D000091344:Filaggrin Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D058977:Molecular Sequence Annotation; D015203:Reproducibility of Results; D015398:Signal Transduction; D060388:Support Vector Machine; D059467:Transcriptome