Screening for key genes associated with atopic dermatitis with DNA microarrays

Zhang,Zhong-Kui; Yang,Yong; Bai,Shu-Rong; Zhang,Gui-Zhen; Liu,Tai‑Hua; Zhou,Zhou; Wang,Chun-Mei; Tang,Li-Jun; Wang,Jun; He,Si-Xian

doi:10.3892/mmr.2014.1908

Screening for key genes associated with atopic dermatitis with DNA microarrays

Authors:
- Zhong-Kui Zhang
- Yong Yang
- Shu-Rong Bai
- Gui-Zhen Zhang
- Tai‑Hua Liu
- Zhou Zhou
- Chun-Mei Wang
- Li-Jun Tang
- Jun Wang
- Si-Xian He
View Affiliations

Affiliations: Department of Dermatology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China, Department of Burns, Plastic Surgery, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China, Department of Anesthesiology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China, Department of Information, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
Published online on: January 21, 2014 https://doi.org/10.3892/mmr.2014.1908
Pages: 1049-1055

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to identify key genes associated with atopic dermatitis (AD) using microarray data and bioinformatic analyses. The dataset GSE6012, downloaded from the Gene Expression Omnibus (GEO) database, contains gene expression data from 10 AD skin samples and 10 healthy skin samples. Following data preprocessing, differentially expressed genes (DEGs) were identified using the limma package of the R project. Interaction networks were constructed comprising DEGs that showed a degree of node of >3, >5 and >10, using the Osprey software. Functional enrichment and pathway enrichment analysis of the network comprising all DEGs and of the network comprising DEGs with a high degree of node, were performed with the DAVID and WebGestalt toolkits, respectively. A total of 337 DEGs were identified. The functional enrichment analysis revealed that the list of DEGs was significantly enriched for proteins related to epidermis development (P=2.95E-07), including loricrin (LOR), keratin 17 (KRT17), small proline-rich repeat proteins (SPRRs) and involucrin (IVL). The chemokine signaling pathway was the most significantly enriched pathway (P=0.0490978) in the network of all DEGs and in the network consisting of high degree‑node DEGs (>10), which comprised the genes coding for chemokine receptor 7 (CCR7), chemokine ligand (CCL19), signal transducer and activator of transcription 1 (STAT1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1). In conclusion, the list of AD-associated proteins identified in this study, including LOR, KRT17, SPRRs, IVL, CCR7, CCL19, PIK3R1 and STAT1 may prove useful for the development of methods to treat AD. From these proteins, PIK3R1 and KRT17 are novel and promising targets for AD therapy.

View Figures

View References

1	Spergel JM and Paller AS: Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 112:S118–S127. 2003. View Article : Google Scholar : PubMed/NCBI
2	Leung DY: Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol. 105:860–876. 2000. View Article : Google Scholar : PubMed/NCBI
3	Laughter D, Istvan JA, Tofte SJ and Hanifin JM: The prevalence of atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol. 43:649–655. 2000. View Article : Google Scholar : PubMed/NCBI
4	Johansson SG, Bieber T, Dahl R, et al: Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 113:832–836. 2004. View Article : Google Scholar : PubMed/NCBI
5	Beltrani VS: Atopic dermatitis: an update. J Allergy Clin Immunol. 104:S85–S86. 1999. View Article : Google Scholar : PubMed/NCBI
6	McGirt LY and Beck LA: Innate immune defects in atopic dermatitis. J Allergy Clin Immunol. 118:202–208. 2006. View Article : Google Scholar : PubMed/NCBI
7	De Benedetto A, Agnihothri R, McGirt LY, Bankova LG and Beck LA: Atopic dermatitis: a disease caused by innate immune defects? J Invest Dermatol. 129:14–30. 2009.PubMed/NCBI
8	Novak N, Bieber T and Leung DY: Immune mechanisms leading to atopic dermatitis. J Allergy Clin Immunol. 112:S128–S139. 2003. View Article : Google Scholar : PubMed/NCBI
9	Akdis CA, Akdis M, Bieber T, et al: Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Allergy. 61:969–987. 2006. View Article : Google Scholar
10	Leung DY: Atopic dermatitis: immunobiology and treatment with immune modulators. Clin Exp Immunol. 107(Suppl 1): 25–30. 1997.PubMed/NCBI
11	Toda M and Ono SJ: Genomics and proteomics of allergic disease. Immunology. 106:1–10. 2002. View Article : Google Scholar : PubMed/NCBI
12	Morar N, Willis-Owen SA, Moffatt MF and Cookson WO: The genetics of atopic dermatitis. J Allergy Clin Immunol. 118:24–34. 2006. View Article : Google Scholar
13	Park YD, Kim SY, Jang HS, et al: Towards a proteomic analysis of atopic dermatitis: a two-dimensional-polyacrylamide gel electrophoresis/mass spectrometric analysis of cultured patient-derived fibroblasts. Proteomics. 4:3446–3455. 2004. View Article : Google Scholar : PubMed/NCBI
14	Merryman-Simpson AE, Wood SH, Fretwell N, et al: Gene (mRNA) expression in canine atopic dermatitis: microarray analysis. Vet Dermatol. 19:59–66. 2008. View Article : Google Scholar : PubMed/NCBI
15	Nomura I, Gao B, Boguniewicz M, Darst MA, Travers JB and Leung DY: Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J Allergy Clin Immunol. 112:1195–1202. 2003. View Article : Google Scholar : PubMed/NCBI
16	Olsson M, Broberg A, Jernas M, et al: Increased expression of aquaporin 3 in atopic eczema. Allergy. 61:1132–1137. 2006. View Article : Google Scholar : PubMed/NCBI
17	Mobini R, Andersson BA, Erjefalt J, et al: A module-based analytical strategy to identify novel disease-associated genes shows an inhibitory role for interleukin 7 receptor in allergic inflammation. BMC Syst Biol. 3:192009. View Article : Google Scholar
18	Williams H, Jburney P, Hay R, et al: The U.K. Working Party’s diagnostic criteria for atopic dermatitis. I Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 131:383–396. 1994.
19	Troyanskaya O, Cantor M, Sherlock G, et al: Missing value estimation methods for DNA microarrays. Bioinformatics. 17:520–525. 2001. View Article : Google Scholar : PubMed/NCBI
20	Fujita A, Sato JR, Rodrigues Lde O, Ferreira CE and Sogayar MC: Evaluating different methods of microarray data normalization. BMC Bioinformatics. 7:4692006. View Article : Google Scholar : PubMed/NCBI
21	Smyth GK: Limma: linear models for microarray data. Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Gentleman R, Carey V, Huber W, Irizarry R and Dudoit S: Springer; New York: pp. 397–420. 2005, View Article : Google Scholar
22	Dudoit S, Schaffer J and Boldrick J: Multiple hypothesis testing in microarray experiments. Statist Sci. 18:71–103. 2003. View Article : Google Scholar
23	Breitkreutz BJ, Stark C and Tyers M: Osprey: a network visualization system. Genome Biol. 4:R222003. View Article : Google Scholar : PubMed/NCBI
24	Willis RC and Hogue CW: Searching, viewing, and visualizing data in the Biomolecular Interaction Network Database (BIND). Curr Protoc Bioinformatics. Chapter 8(Unit 8.9)2006. View Article : Google Scholar
25	Breitkreutz BJ, Stark C and Tyers M: The GRID: the general repository for interaction datasets. Genome Biol. 4:R232003. View Article : Google Scholar : PubMed/NCBI
26	Estrada E: Virtual identification of essential proteins within the protein interaction network of yeast. Proteomics. 6:35–40. 2006. View Article : Google Scholar : PubMed/NCBI
27	Jeong H, Mason SP, Barabasi AL and Oltvai ZN: Lethality and centrality in protein networks. Nature. 411:41–42. 2001. View Article : Google Scholar : PubMed/NCBI
28	Huang da W, Sherman BT and Lempicki RA: Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 4:44–57. 2009.PubMed/NCBI
29	Zhang B, Kirov S and Snoddy J: WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res. 33:W741–W748. 2005. View Article : Google Scholar : PubMed/NCBI
30	Duncan D, Prodduturi N and Zhang B: WebGestalt2: an updated and expanded version of the Web-based Gene Set Analysis Toolkit. BMC Bioinformatics. 11:1. 2010. View Article : Google Scholar
31	Kim BE, Leung DYM, Boguniewicz M and Howell MD: Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 126:332–337. 2008. View Article : Google Scholar : PubMed/NCBI
32	Nakai K, Yoneda K, Hosokawa Y, et al: Reduced expression of epidermal growth factor receptor, E-cadherin, and occludin in the skin of flaky tail mice is due to filaggrin and loricrin deficiencies. Am J Pathol. 181:969–977. 2012. View Article : Google Scholar : PubMed/NCBI
33	Sevilla LM, Nachat R, Groot KR, et al: Mice deficient in involucrin, envoplakin, and periplakin have a defective epidermal barrier. J Cell Biol. 179:1599–1612. 2007. View Article : Google Scholar : PubMed/NCBI
34	Komine M, Freedberg IM and Blumenberg M: Regulation of epidermal expression of keratin K17 in inflammatory skin diseases. J Invest Dermatol. 107:569–575. 1996. View Article : Google Scholar : PubMed/NCBI
35	Hobbs RP, Lessard JC and Coulombe PA: Keratin intermediate filament proteins - novel regulators of inflammation and immunity in skin. J Cell Sci. 125:5257–5258. 2012. View Article : Google Scholar : PubMed/NCBI
36	Depianto D, Kerns ML, Dlugosz AA and Coulombe PA: Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin. Nat Genet. 42:910–914. 2010. View Article : Google Scholar : PubMed/NCBI
37	Theerawatanasirikul S, Sailasuta A, Thanawongnuwech R and Suriyaphol G: Alterations of keratins, involucrin and filaggrin gene expression in canine atopic dermatitis. Res Vet Sci. 93:1287–1292. 2012. View Article : Google Scholar : PubMed/NCBI
38	Hohl D, de Viragh PA, Amiguet-Barras F, Gibbs S, Backendorf C and Huber M: The small proline-rich proteins constitute a multigene family of differentially regulated cornified cell envelope precursor proteins. J Invest Dermatol. 104:902–909. 1995. View Article : Google Scholar : PubMed/NCBI
39	Zimmermann N, Doepker MP, Witte DP, et al: Expression and regulation of small proline-rich protein 2 in allergic inflammation. Am J Respir Cell Mol Biol. 32:428–435. 2005. View Article : Google Scholar : PubMed/NCBI
40	Sallusto F: The role of chemokine receptors in primary, effector and memory immune response. Exp Dermatol. 11:476–478. 2002. View Article : Google Scholar
41	Kakinuma T, Saeki H, Tsunemi Y, et al: Increased serum cutaneous T cell-attracting chemokine (CCL27) levels in patients with atopic dermatitis and psoriasis vulgaris. J Allergy Clin Immunol. 111:592–597. 2003. View Article : Google Scholar : PubMed/NCBI
42	Gunther C, Bello-Fernandez C, Kopp T, et al: CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells. J Immunol. 174:1723–1728. 2005. View Article : Google Scholar : PubMed/NCBI
43	Shimada Y, Takehara K and Sato S: Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis. J Dermatol Sci. 34:201–208. 2004. View Article : Google Scholar : PubMed/NCBI
44	Heishi M, Kagaya S, Katsunuma T, et al: High-density oligonucleotide array analysis of mRNA transcripts in peripheral blood cells of severe atopic dermatitis patients. Int Arch Allergy Immunol. 129:57–66. 2002. View Article : Google Scholar : PubMed/NCBI
45	Suarez-Farinas M, Tintle SJ, Shemer A, et al: Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol. 127:954–964. 2011. View Article : Google Scholar : PubMed/NCBI
46	Parvaneh N, Casanova JL, Notarangelo LD and Conley ME: Primary immunodeficiencies: a rapidly evolving story. J Allergy Clin Immunol. 131:314–323. 2013. View Article : Google Scholar : PubMed/NCBI
47	Watanabe O, Tamari M, Natori K, et al: Loci on murine chromosomes 7 and 13 that modify the phenotype of the NOA mouse, an animal model of atopic dermatitis. J Hum Genet. 46:221–224. 2001. View Article : Google Scholar : PubMed/NCBI
48	Heinzmann A and Daser A: Mouse models for the genetic dissection of atopy. Int Arch Allergy Immunol. 127:170–180. 2002. View Article : Google Scholar : PubMed/NCBI