Integrated microarray analysis provided novel insights to the pathogenesis of glaucoma

Wang,Jinhui; Qu,Daofei; An,Jinghong; Yuan,Guoming; Liu,Yufu

doi:10.3892/mmr.2017.7711

Integrated microarray analysis provided novel insights to the pathogenesis of glaucoma

Authors:
- Jinhui Wang
- Daofei Qu
- Jinghong An
- Guoming Yuan
- Yufu Liu
View Affiliations

Affiliations: Department of Clinical Laboratory, The First Hospital of Harbin, Harbin, Heilongjiang 150001, P.R. China, Department of Ophthalmology, The First Hospital of Harbin, Harbin, Heilongjiang 150001, P.R. China
Published online on: October 4, 2017 https://doi.org/10.3892/mmr.2017.7711
Pages: 8735-8746
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Glaucoma is characterized as a visual field defect, which is the second most common cause of blindness. The present study performed an integrated analysis of microarray studies of glaucoma derived from Gene Expression Omnibus (GEO). Following the identification of the differentially expressed genes (DEGs) in glaucoma compared with normal control (NC) tissues, the functional annotation, glaucoma‑specific protein‑protein interaction (PPI) network and transcriptional regulatory network constructions were performed. The acute intraocular pressure (IOP) elevation rat models were established and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was performed for DEGs expression confirmation. Three datasets were downloaded from GEO. A total of 97 DEGs, 82 upregulated and 15 downregulated were identified in glaucoma compared with NC groups with false discovery rate <0.05. Response to virus and immune response were two significantly enriched GO terms in glaucoma. Valine, leucine and isoleucine degradation was a significantly enriched pathway of DEGs in glaucoma. According to the PPI network, HDAC1, HBN, UBR4 and PDK1 were hub proteins in glaucoma. FOXD3, HNF‑4 and AP‑1 were the three transcription factors (TFs) derived from top 10 TFs which covered the majority of downstream DEGs in glaucoma. Based on the RT‑qPCR results, the expression levels of 3 DEGs, raftlin, lipid raft linker 1 (RFTN1), PBX homeobox 1 (PBX1), HDAC1 were significantly upregulated and the expression of GEM was significantly downregulated in acute IOP elevation rat model at the first and fifth day. These four DEGs had the same expression pattern with our integrated analysis. Therefore, the current study concluded that 6 DEGs, including HEPH, SELENBP1, RFTN1, ID1, HDAC‑1 and PBX1 and three TFs, including FOXD3, HNF‑4 and AP‑1 may be involved with the pathogenesis of glaucoma. The findings of the current study may improve diagnosis and drug design for glaucoma.

View Figures

View References

1	Yu-Wai-Man P, Stewart JD, Hudson G, Andrews RM, Griffiths PG, Birch MK and Chinnery PF: OPA1 increases the risk of normal but not high tension glaucoma. J Med Genet. 47:120–125. 2010. View Article : Google Scholar : PubMed/NCBI
2	Moreno MC, Sande P, Marcos HA, de Zavalía N, Sarmiento MI Keller and Rosenstein RE: Effect of glaucoma on the retinal glutamate/glutamine cycle activity. FASEB J. 19:1161–1162. 2005.PubMed/NCBI
3	Liu T, Xie L, Ye J and He X: Family-based analysis identified CD2 as a susceptibility gene for primary open angle glaucoma in Chinese Han population. J Cell Mol Med. 18:600–609. 2014. View Article : Google Scholar : PubMed/NCBI
4	Guo MS, Wu YY and Liang ZB: Hyaluronic acid increases MMP-2 and MMP-9 expressions in cultured trabecular meshwork cells from patients with primary open-angle glaucoma. Mol Vis. 18:1175–1181. 2012.PubMed/NCBI
5	Gazzard G, Foster PJ, Devereux JG, Oen F, Chew P, Khaw PT and Seah S: Intraocular pressure and visual field loss in primary angle closure and primary open angle glaucomas. Br J Ophthalmol. 87:720–725. 2003. View Article : Google Scholar : PubMed/NCBI
6	Rosenberg LF: Glaucoma: Early detection and therapy for prevention of vision loss. Am Fam Physician. 52:2289–2298. 1995.PubMed/NCBI
7	Bikbova G, Oshitari T and Yamamoto S: Diabetes mellitus and retinal vein occlusion as risk factors for open angle glaucoma and neuroprotective therapies for retinal ganglion cell neuropathy. J Clin Exper Ophthalmol. S3:2012.
8	McMenemy MG: Primary Open Angle Glaucoma. Springer; New York, NY: pp. 1721. 2014
9	Girard MJA, Zimmo L, White ET, Mari JM, Ethier CR and Strouthidis NG: Towards a biomechanically-based diagnosis for glaucoma: In vivo deformation mapping of the human optic nerve head. In: ASME 2012 Summer Bioengineering Conference. Puerto Rico. pp. 423–424. 2012;
10	Wu Y, Zang WD and Jiang W: Functional analysis of differentially expressed genes associated with glaucoma from DNA microarray data. Genet Mol Res. 13:9421–9428. 2014. View Article : Google Scholar : PubMed/NCBI
11	Lukas TJ, Miao H, Chen L, Riordan SM, Li W, Crabb AM, Wise A, Du P, Lin SM and Hernandez MR: Susceptibility to glaucoma: Differential comparison of the astrocyte transcriptome from glaucomatous African American and Caucasian American donors. Genome Biol. 9:R1112008. View Article : Google Scholar : PubMed/NCBI
12	Hernandez MR, Agapova OA, Yang P, Salvador-Silva M, Ricard CS and Aoi S: Differential gene expression in astrocytes from human normal and glaucomatous optic nerve head analyzed by cDNA microarray. Glia. 38:45–64. 2002. View Article : Google Scholar : PubMed/NCBI
13	Yan X, Yuan F, Chen X and Dong C: Bioinformatics analysis to identify the differentially expressed genes of glaucoma. Mol Med Rep. 12:4829–4836. 2015. View Article : Google Scholar : PubMed/NCBI
14	Rozsa FW, Scott KM, Pawar H, Samples JR, Wirtz MK and Richards JE: Differential expression profile prioritization of positional candidate glaucoma genes: The GLC1C locus. Arch Ophthalmol. 125:117–127. 2007. View Article : Google Scholar : PubMed/NCBI
15	Fei Q, Lin J, Meng H, Wang B, Yang Y, Wang Q, Su N, Li J and Li D: Identification of upstream regulators for synovial expression signature genes in osteoarthritis. Joint Bone Spine. 83:545–551. 2016. View Article : Google Scholar : PubMed/NCBI
16	Marot G, Foulley JL, Mayer CD and Jaffrézic F: Moderated effect size and P-value combinations for microarray meta-analyses. Bioinformatics. 25:2692–2696. 2009. View Article : Google Scholar : PubMed/NCBI
17	Wei K, Pan S and Li Y: Functional characterization of maize C₂H₂, zinc-finger gene family. Plant Mol Biol Rep. 34:761–776. 2016. View Article : Google Scholar
18	Matys V, Fricke E, Geffers R, Gössling E, Haubrock M, Hehl R, Hornischer K, Karas D, Kel AE, Kel-Margoulis OV, et al: TRANSFAC: Transcriptional regulation, from patterns to profiles. Nucleic Acids Res. 31:374–378. 2003. View Article : Google Scholar : PubMed/NCBI
19	Adachi M, Takahashi K, Nishikawa M, Miki H and Uyama M: High intraocular pressure-induced ischemia and reperfusion injury in the optic nerve and retina in rats. Graefes Arch Clin Exp Ophthalmol. 234:445–451. 1996. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Adachi M, Takahashi K, Nishikawa M, Miki H and Uyama M: High intraocular pressure-induced ischemia and reperfusion injury in the optic nerve and retina in rats. Graefes Arch Clin Exp Ophthalmol. 234:445–451. 1996. View Article : Google Scholar : PubMed/NCBI
22	Huang Y, Li Z, Wang N, van Rooijen N and Cui Q: Roles of PI3K and JAK pathways in viability of retinal ganglion cells after acute elevation of intraocular pressure in rats with different autoimmune backgrounds. BMC Neurosci. 9:782008. View Article : Google Scholar : PubMed/NCBI
23	Zhang S, Wang H, Lu Q, Qing G, Wang N, Wang Y, Li S, Yang D and Yan F: Detection of early neuron degeneration and accompanying glial responses in the visual pathway in a rat model of acute intraocular hypertension. Brain Res. 1303:131–143. 2009. View Article : Google Scholar : PubMed/NCBI
24	Sun D, Qu J and Jakobs TC: Reversible reactivity by optic nerve astrocytes. Glia. 61:1218–1235. 2013. View Article : Google Scholar : PubMed/NCBI
25	Lye-Barthel M, Sun D and Jakobs TC: Morphology of astrocytes in a glaucomatous optic nerve. Invest Ophthalmol Vis Sci. 54:909–917. 2013. View Article : Google Scholar : PubMed/NCBI
26	Morrison JC, Cepurna WO, Doser TA, Dyck JA and Johnson EC: A short interval of controlled elevation of iop (CEI) reproduces early chronic glaucoma model optic nerve head (ONH) gene expression responses. Invest Ophthalmol Vis Sci. 51:52162010.
27	Morrison JC, Cepurna WO, Tehrani S, Choe TE, Jayaram H, Lozano DC, Fortune B and Johnson EC: A period of controlled elevation of IOP (CEI) produces the specific gene expression responses and focal injury pattern of experimental rat glaucoma. Invest Ophthalmol Vis Sci. 57:6700–6711. 2016. View Article : Google Scholar : PubMed/NCBI
28	Downs JC, Burgoyne CF, Seigfreid WP, Reynaud JF, Strouthidis NG and Sallee V: 24-hour IOP telemetry in the nonhuman primate: Implant system performance and initial characterization of IOP at multiple timescales. Invest Ophthalmol Vis Sci. 52:7365–7375. 2011. View Article : Google Scholar : PubMed/NCBI
29	Crowston JG, Kong YX, Trounce IA, Dang TM, Fahy ET, Bui BV, Morrison JC and Chrysostomou V: An acute intraocular pressure challenge to assess retinal ganglion cell injury and recovery in the mouse. Exp Eye Res. 141:3–8. 2015. View Article : Google Scholar : PubMed/NCBI
30	Briggs EL Ashworth, Toh T, Eri R, Hewitt AW and Cook AL: TIMP1, TIMP2 and TIMP4 are increased in aqueous humor from primary open angle glaucoma patients. Mol Vis. 21:1162–1172. 2015.PubMed/NCBI
31	Janssen SF, Gorgels TG, Van der Spek PJ, Jansonius NM and Bergen AA: In silico analysis of the molecular machinery underlying aqueous humor production: Potential implications for glaucoma. J Clin Bioinforma. 3:212013. View Article : Google Scholar : PubMed/NCBI
32	Chen JH, Wang D, Huang C, Zheng Y, Chen H, Pang CP and Zhang M: Interactive effects of ATOH7 and RFTN1 in association with adult-onset primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 53:779–785. 2012. View Article : Google Scholar : PubMed/NCBI
33	Macgregor S, Hewitt AW, Hysi PG, Ruddle JB, Medland SE, Henders AK, Gordon SD, Andrew T, McEvoy B, Sanfilippo PG, et al: Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet. 19:2716–2724. 2010. View Article : Google Scholar : PubMed/NCBI
34	Xue W, Du P, Lin S, Dudley VJ, Hernandez MR and Sarthy VP: Gene expression changes in retinal Müller (glial) cells exposed to elevated pressure. Curr Eye Res. 36:754–767. 2011. View Article : Google Scholar : PubMed/NCBI
35	Futterweit W, Ritch R, Teekhasaenee C and Nelson ES: Coexistence of Prader-Willi syndrome, congenital ectropion uveae with glaucoma, and factor XI deficiency. JAMA. 255:3280–3282. 1986. View Article : Google Scholar : PubMed/NCBI
36	Schmitt HM, Schlamp CL and Nickells RW: Role of HDACs in optic nerve damage-induced nuclear atrophy of retinal ganglion cells. Neurosci Lett. 625:11–15. 2016. View Article : Google Scholar : PubMed/NCBI
37	Ueki Y and Reh TA: Activation of BMP-Smad1/5/8 signaling promotes survival of retinal ganglion cells after damage in vivo. PLoS One. 7:e386902012. View Article : Google Scholar : PubMed/NCBI
38	Biermann J, Boyle J, Pielen A and Lagrèze WA: Histone deacetylase inhibitors sodium butyrate and valproic acid delay spontaneous cell death in purified rat retinal ganglion cells. Mol Vis. 17:395–403. 2011.PubMed/NCBI
39	Chindasub P, Lindsey JD, Duong-Polk K, Leung CK and Weinreb RN: Inhibition of histone deacetylases 1 and 3 protects injured retinal ganglion cells. Invest Ophthalmol Vis Sci. 54:96–102. 2013. View Article : Google Scholar : PubMed/NCBI
40	Messina-Baas OM, González-Huerta LM, Chima-Galán C, Kofman-Alfaro SH, Rivera-Vega MR, Babayán-Mena I and Cuevas-Covarrubias SA: Molecular analysis of the CYP1B1 gene: Identification of novel truncating mutations in patients with primary congenital glaucoma. Ophthalmic Res. 39:17–23. 2007. View Article : Google Scholar : PubMed/NCBI
41	Mansergh FC, Kenna PF, Ayuso C, Kiang AS, Humphries P and Farrar GJ: Novel mutations in the TIGR gene in early and late onset open angle glaucoma. Hum Mutat. 11:244–251. 1998. View Article : Google Scholar : PubMed/NCBI
42	Nakamura M: New insights into the pathogenesis of glaucomatous optic neuropathy and refinement of the objective assessment of its functional damage. Nippon Ganka Gakkai Zasshi. 116:298–344. 2012.PubMed/NCBI
43	Sowden JC: Molecular and developmental mechanisms of anterior segment dysgenesis. Eye. 21:1310–1318. 2007. View Article : Google Scholar : PubMed/NCBI
44	Kloss BA, Reis LM, Brémond-Gignac D, Glaser T and Semina EV: Analysis of FOXD3 sequence variation in human ocular disease. Mol Vis. 18:1740–1749. 2012.PubMed/NCBI
45	Lehmann OJ, Ebenezer ND, Jordan T, Fox M, Ocaka L, Payne A, Leroy BP, Clark BJ, Hitchings RA, Povey S, et al: Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma. Am J Hum Genet. 67:1129–1135. 2000. View Article : Google Scholar : PubMed/NCBI
46	Chakrabarti S, Kaur K, Rao KN, Mandal AK, Kaur I, Parikh RS and Thomas R: The transcription factor gene FOXC1 exhibits a limited role in primary congenital glaucoma. Invest Ophthalmol Vis Sci. 50:75–83. 2009. View Article : Google Scholar : PubMed/NCBI