Identification of pathogenic genes and transcription factors in glaucoma

  • Authors:
    • Jie Feng
    • Jing Xu
  • View Affiliations

  • Published online on: May 14, 2019
  • Pages: 216-224
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Glaucoma is a group of eye diseases characterized by alterations in the contour of the optic nerve head, with corresponding visual field defects and progressive loss of retinal ganglion cells. The present study aimed to identify the key genes and upstream regulators in glaucoma. To screen the pathogenic genes involved in glaucoma, an integrated analysis was performed by using the microarray datasets in glaucoma derived from the Gene Expression Omnibus (GEO) database. The functional annotation and potential pathways of differentially expressed genes (DEGs) were additionally examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A glaucoma‑specific transcriptional regulatory network was constructed to identify crucial transcriptional factors that target the DEGs in glaucoma. From two GEO datasets, 1,935 DEGs (951 upregulated and 984 downregulated genes) between glaucoma and normal controls were identified. GO and KEGG analyses identified that ‘eye development’ [false discovery rate (FDR)=0.00415533] and ‘visual perception’ (FDR=0.00713283) were significantly enriched pathways for DEGs. The expression of lipocalin 2 (LCN2), monoamine oxidase A (MAOA), hemoglobin subunit β (HBB), paired box 6 (PAX6), fibronectin (FN1) and cAMP responsive element binding protein 1 (CREB1) were demonstrated to be involved in the pathogenesis of glaucoma. In conclusion, LCN2, MAOA, HBB, PAX6, FN1 and CREB1 may serve roles in glaucoma, regulated by PAX4, solute carrier family 22 member 1, hepatocyte nuclear factor 4 α and ELK1, ETS transcription factor. These data may contribute to the development of novel potential biomarkers, reveal the underlying pathogenesis and additionally identify novel therapeutic targets for glaucoma.



Tham YC, Li X, Wong TY, Quigley HA, Aung T and Cheng CY: Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis. Ophthalmology. 121:20812014. View Article : Google Scholar : PubMed/NCBI


Anshu A, Price MO, Richardson MR, Segu ZM, Lai X, Yoder MC and Price FW Jr: Alterations in the aqueous humor proteome in patients with a glaucoma shunt device. Mol Vis. 17:1891–1900. 2011.PubMed/NCBI


Saccà SC, Gandolfi S, Bagnis A, Manni G, Damonte G, Traverso CE and Izzotti A: From DNA damage to functional changes of the trabecular meshwork in aging and glaucoma. Ageing Res Rev. 29:26–41. 2016. View Article : Google Scholar : PubMed/NCBI


Kayange PC, Nkume HB, Feyi-Waboso A, Kalua K, Msukwa G and Schwering Schulze M: Presentation of primary open angle glaucoma (POAG) at lions sight first eye hospital in Blantyre, Malawi. Malawi Med J. 26:60–62. 2014.PubMed/NCBI


Kwon YH, Fingert JH, Kuehn MH and Alward WL: Primary open-angle glaucoma. N Engl J Med. 2:1113–1124. 2009. View Article : Google Scholar


Nazir S, Mukhtar M, Shahnawaz M, Farooqi S, Fatima N, Mehmood R and Sheikh N: A novel single nucleotide polymorphism in exon 3 of MYOC enhances the risk of glaucoma. PLoS One. 13:e01951572018. View Article : Google Scholar : PubMed/NCBI


Huang C, Xie L, Wu Z, Cao Y, Zheng Y, Pang CP and Zhang M: Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing. Sci Rep. 8:44982018. View Article : Google Scholar : PubMed/NCBI


Fingert JH, Robin AL, Stone JL, Roos BR, Davis LK, Scheetz TE, Bennett SR, Wassink TH, Kwon YH, Alward WL, et al: Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum Mol Genet. 20:2482–2494. 2011. View Article : Google Scholar : PubMed/NCBI


Kawase K, Allingham RR, Meguro A, Mizuki N, Roos B, Solivan-Timpe FM, Robin AL, Ritch R and Fingert JH: Confirmation of TBK1 duplication in normal tension glaucoma. Exp Eye Res. 96:178–180. 2012. View Article : Google Scholar : PubMed/NCBI


Ritch R, Darbro B, Menon G, Khanna CL, Solivan-Timpe F, Roos BR, Sarfarzi M, Kawase K, Yamamoto T, Robin AL, et al: TBK1 gene duplication and normal-tension glaucoma. JAMA Ophthalmol. 132:544–548. 2014. View Article : Google Scholar : PubMed/NCBI


Burdon KP, Macgregor S, Hewitt AW, Sharma S, Chidlow G, Mills RA, Danoy P, Casson R, Viswanathan AC, Liu JZ, et al: Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet. 43:574–578. 2011. View Article : Google Scholar : PubMed/NCBI


Yasuda M, Tanaka Y, Omodaka K, Nishiguchi KM, Nakamura O, Tsuda S and Nakazawa T: Transcriptome profiling of the rat retina after optic nerve transection. Sci Rep. 6:287362016. View Article : Google Scholar : PubMed/NCBI


Shi Z, Rudzinski M, Meerovitch K, Lebrun-Julien F, Birman E, Di Polo A and Saragovi HU: Alpha2-macroglobulin is a mediator of retinal ganglion cell death in glaucoma. J Biol Chem. 283:29156–29165. 2008. View Article : Google Scholar : PubMed/NCBI


Konstas AG, Maskaleris G, Gratsonidis S and Sardelli C: Compliance and viewpoint of glaucoma patients in greece. Eye (Lond). 14:752–756. 2000. View Article : Google Scholar : PubMed/NCBI


Tajiri-Utagawa E, Hara M, Takahashi K, Watanabe M and Wakita T: Development of a rapid high-throughput method for high-resolution melting analysis for routine detection and genotyping of noroviruses. J Clin Microbiol. 47:435–440. 2009. View Article : Google Scholar : PubMed/NCBI


Chang WS, Wang YH, Zhu XT and Wu CJ: Genome-wide profiling of miRNA and mRNA expression in Alzheimer's disease. Med Sci Monit. 23:2721–2731. 2017. View Article : Google Scholar : PubMed/NCBI


Liu Y, Allingham RR, Qin X, Layfield D, Dellinger AE, Gibson J, Wheeler J, Ashley-Koch AE, Stamer WD and Hauser MA: Gene expression profile in human trabecular meshwork from patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci Sep. 54:6382–6389. 2013. View Article : Google Scholar


Liton PB, Luna C, Challa P, Epstein DL and Gonzalez P: Genome-wide expression profile of human trabecular meshwork cultured cells, nonglaucomatous and primary open angle glaucoma tissue. Mol Vis. 12:774–790. 2006.PubMed/NCBI


Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, et al: NCBI GEO: Archive for functional genomics data sets-update. Nucleic Acids Rese 41 (Database Issue). D991–D995. 2013.


Li JJ, Wang BQ, Fei Q, Yang Y and Li D: Identification of candidate genes in osteoporosis by integrated microarray analysis. Bone Joint Res. 5:594–601. 2016. View Article : Google Scholar : PubMed/NCBI


Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W and Smyth GK: limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43:e472015. View Article : Google Scholar : PubMed/NCBI


Klipper-Aurbach Y, Wasserman M, Braunspiegel-Weintrob N, Borstein D, Peleg S, Assa S, Karp M, Benjamini Y, Hochberg Y and Laron Z: Mathematical formulae for the prediction of the residual beta cell function during the first two years of disease in children and adolescents with insulin-dependent diabetes mellitus. Med Hypotheses. 45:486–490. 1995. View Article : Google Scholar : PubMed/NCBI


Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: Tool for the unification of biology. The gene ontology consortium. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI


Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI


Wang F, Wang R, Li Q, Qu X, Hao Y, Yang J, Zhao H, Wang Q, Li G, Zhang F, et al: A transcriptome profile in hepatocellular carcinomas based on integrated analysis of microarray studies. Diagn Pathol. 12:42017. View Article : Google Scholar : PubMed/NCBI


Dufier JL, Rozet JM, Kaplan J and Roche O: From congenital glaucoma to chronic open angle glaucoma in adulthood: A clinical and genetic continuum. Bull Acad Natl Med. 197:133–141. 2013.PubMed/NCBI


Wang X, Huai G, Wang H, Liu Y, Qi P, Shi W, Peng J, Yang H, Deng S and Wang Y: Mutual regulation of the Hippo/Wnt/LPA/TGF-β signaling pathways and their roles in glaucoma (review). Int J Mol Med. 41:1201–1212. 2018.PubMed/NCBI


Alpízar-Alpízar W, Laerum OD, Illemann M, Ramírez JA, Arias A, Malespín-Bendaña W, Ramírez V, Lund LR, Borregaard N and Nielsen BS: Neutrophil gelatinase-associated lipocalin (NGAL/Lcn2) is upregulated in gastric mucosa infected with Helicobacter pylori. Virchows Archiv. 455:225–233. 2009. View Article : Google Scholar : PubMed/NCBI


Khalyfa A, Chlon T, Qiang H, Agarwal N and Cooper NG: Microarray reveals complement components are regulated in the serum-deprived rat retinal ganglion cell line. Mol Vis. 13:293–308. 2007.PubMed/NCBI


Maeda I, Ueda T, Koide R, Inatomi M, Fukado Y, Uchida E, Oguchi K and Yasuhara H: Ocular hypotensive effects of monoamine oxidase-a inhibitors in rabbit. Jpn J Ophthalmol. 32:211–218. 1988.PubMed/NCBI


Ajmone-Cat MA, De Simone R, Nicolini A and Minghetti L: Effects of phosphatidylserine on p38 mitogen activated protein kinase, cyclic AMP responding element binding protein and nuclear factor-kappaB activation in resting and activated microglial cells. J Neurochem. 84:413–416. 2003. View Article : Google Scholar : PubMed/NCBI


Walton M, Woodgate AM, Muravlev A, Xu R, During MJ and Dragunow M: CREB phosphorylation promotes nerve cell survival. J Neurochem. 73:1836–1842. 1999.PubMed/NCBI


Shao Y, Yu Y, Zhou Q, Li C, Yang L and Pei CG: Inhibition of miR-134 protects against hydrogen peroxide-induced apoptosis in retinal ganglion cells. J Mol Neurosci. 56:461–471. 2015. View Article : Google Scholar : PubMed/NCBI


Pankov R and Yamada KM: Fibronectin at a glance. J Cell Sci. 115:3861–3863. 2002. View Article : Google Scholar : PubMed/NCBI


Yi W, Xiao E, Ding R, Luo P and Yang Y: High expression of fibronectin is associated with poor prognosis, cell proliferation and malignancy via the NF-κB/p53-apoptosis signaling pathway in colorectal cancer. Oncol Rep. 36:3145–3153. 2016. View Article : Google Scholar : PubMed/NCBI


Jun HK, Jung YJ and Choi BK: Inflammasome activators induce fibronectin expression and release in macrophages. Cell Microbiol. 19:2017. View Article : Google Scholar : PubMed/NCBI


Jeong JK, Ryu BJ, Choi J, Kim DH, Choi EJ, Park JW, Park JJ and Lee BJ: NELL2 participates in formation of the sexually dimorphic nucleus of the pre-optic area in rats. J Neurochem. 106:1604–1613. 2008. View Article : Google Scholar : PubMed/NCBI


Halder G, Callaerts P and Gehring WJ: Induction of ectopic eyes by targeted expression of the eyeless gene in Drosophila. Science. 267:1788–1792. 1995. View Article : Google Scholar : PubMed/NCBI


Wawersik S and Maas RL: Vertebrate eye development as modeled in Drosophila. Hum Mol Genet. 9:917–925. 2000. View Article : Google Scholar : PubMed/NCBI


Fujimura N, Klimova L, Antosova B, Smolikova J, Machon O and Kozmik Z: Genetic interaction between Pax6 and β-catenin in the developing retinal pigment epithelium. Dev Genes Evol. 225:121–128. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

July 2019
Volume 20 Issue 1

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Feng, J., & Feng, J. (2019). Identification of pathogenic genes and transcription factors in glaucoma. Molecular Medicine Reports, 20, 216-224.
Feng, J., Xu, J."Identification of pathogenic genes and transcription factors in glaucoma". Molecular Medicine Reports 20.1 (2019): 216-224.
Feng, J., Xu, J."Identification of pathogenic genes and transcription factors in glaucoma". Molecular Medicine Reports 20, no. 1 (2019): 216-224.