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Identification of hub genes and molecular pathways in keratoconus by integrating bioinformatics and literature mining at the RNA level

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Abstract

Objective

Keratoconus (KC) is a condition characterized by progressive corneal steepening and thinning. However, its pathophysiological mechanism remains vague. We mainly performed literature mining to extract bioinformatic and related data on KC at the RNA level. The objective of this study was to explore the potential pathological mechanisms of KC by identifying hub genes and key molecular pathways at the RNA level.

Methods

We performed an exhaustive search of the PubMed database and identified studies that pertained to gene transcripts derived from diverse corneal layers in patients with KC. The identified differentially expressed genes were intersected, and overlap** genes were extracted for further analyses. Significantly enriched genes were screened using “Gene Ontology” (GO) and “Kyoto Encyclopedia of Genes and Genomes” (KEGG) analysis with the “Database for Annotation, Visualization, and Integrated Discovery” (DAVID) database. A protein–protein interaction (PPI) network was constructed for the significantly enriched genes using the STRING database. The PPI network was visualized using the Cytoscape software, and hub genes were screened via betweenness centrality values. Pathways that play a critical role in the pathophysiology of KC were discovered using the GO and KEGG analyses of the hub genes.

Results

68 overlap** genes were obtained. Fifty genes were significantly enriched in 67 biological processes, and 16 genes were identified in 7 KEGG pathways. Moreover, 14 nodes and 32 edges were identified via the PPI network constructed using the STRING database. Multiple analyses identified 4 hub genes, 12 enriched biological processes, and 6 KEGG pathways. GO enrichment analysis showed that the hub genes are mainly involved in the positive regulation of apoptotic process, and KEGG analysis showed that the hub genes are primarily associated with the interleukin-17 (IL-17) and tumor necrosis factor (TNF) pathways. Overall, the matrix metalloproteinase 9, IL-6, estrogen receptor 1, and prostaglandin-endoperoxide synthase 2 were the potential important genes associated with KC.

Conclusion

Four genes, matrix metalloproteinase 9, IL-6, estrogen receptor 1, and prostaglandin endoperoxide synthase 2, as well as IL-17 and TNF pathways, are critical in the development of KC. Inflammation and apoptosis may contribute to the pathogenesis of KC.

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Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

KC:

Keratoconus

GO:

Gene ontology

KEGG:

Kyoto encyclopedia of genes and genomes

DAVID:

Database for annotation, visualization, and integrated discovery

PPI:

Protein–protein interaction

DEGs:

Differentially expressed genes

IL-17:

Interleukin-17

TNF:

Tumor necrosis factor

MMP9:

Matrix metalloproteinase 9

ECM:

Extracellular matrix

TUNEL:

TdT-mediated dUTP Nick-End Labeling

sIL-6R:

Soluble IL-6 receptor

PTGS:

Prostaglandin peroxidase synthases

LOX:

Lysyl oxidases

Erα:

Estrogen receptor alpha

References

  1. Rabinowitz YS (1998) Keratoconus. Surv Ophthalmol 42(4):297–319

    Article  CAS  PubMed  Google Scholar 

  2. Hashemi H, Heydarian S, Hooshmand E, Saatchi M, Yekta A, Aghamirsalim M et al (2020) The prevalence and risk factors for keratoconus: a systematic review and meta-analysis. Cornea 39(2):263–270

    Article  PubMed  Google Scholar 

  3. Rabinowitz YS, Galvis V, Tello A, Rueda D, García JD (2021) Genetics vs chronic corneal mechanical trauma in the etiology of keratoconus. Exp Eye Res 202:108328

    Article  CAS  PubMed  Google Scholar 

  4. Lim L, Lim EWL (2020) Current perspectives in the management of keratoconus with contact lenses. Eye (Lond) 34(12):2175–2196

    Article  PubMed  Google Scholar 

  5. Galvis V, Tello A, Laiton AN, Salcedo SLL (2019) Indications and techniques of corneal transplantation in a referral center in Colombia, South America (2012–2016). Int Ophthalmol 39(8):1723–1733

    Article  PubMed  Google Scholar 

  6. Thanitcul C, Varadaraj V, Canner JK, Woreta FA, Soiberman US, Srikumaran D (2021) Predictors of receiving keratoplasty for keratoconus. Am J Ophthalmol 231:11–18

    Article  PubMed  Google Scholar 

  7. Galvis V, Tello A, Barrera R, Niño CA (2015) Inflammation in keratoconus. Cornea 34(8):e22–e23

    Article  PubMed  Google Scholar 

  8. Nichani PAH, Solomon B, Trinh T, Mimouni M, Rootman D, Singal N et al (2023) Investigating the role of inflammation in keratoconus: a retrospective analysis of 551 eyes. Eur J Ophthalmol 33(1):35–43

    Article  PubMed  Google Scholar 

  9. Sahebjada S, Al-Mahrouqi HH, Moshegov S, Panchatcharam SM, Chan E, Daniell M et al (2021) Eye rubbing in the aetiology of keratoconus: a systematic review and meta-analysis. Graefe’s Arch Clin Exp Ophthalmol 259(8):2057–2067

    Article  Google Scholar 

  10. Shajari M, Eberhardt E, Müller M, Al Khateeb G, Friderich S, Remy M et al (2016) Effects of atopic syndrome on keratoconus. Cornea 35(11):1416–1420

    Article  PubMed  Google Scholar 

  11. Crawford AZ, Zhang J, Gokul A, McGhee CNJ, Ormonde SE (2020) The enigma of environmental factors in keratoconus. Asia-Pac J Ophthalmol (Philadelphia, PA) 9(6):549–556

    Article  Google Scholar 

  12. Cagliari C, Schor P, Formentin L, Lipener C, Dos Santos MS, Oliveira H et al (2022) Corneal response to scleral contact lens wear in keratoconus. Eye Contact Lens 48(8):322–327

    Article  PubMed  Google Scholar 

  13. Gatinel D, Galvis V, Tello A, Niño CA, Rey JJ, Camacho PA et al (2020) Obstructive sleep Apnea-Hypopnea syndrome and keratoconus: an epiphenomenon related to sleep position? Cornea 39(4):e11–e12

    Article  PubMed  Google Scholar 

  14. Bitton K, Dubois M, Moran S, Gatinel D (2022) Discordant keratoconus in monozygotic twins. Case Rep Ophthalmol 13(1):313–317

    Article  PubMed  PubMed Central  Google Scholar 

  15. di Martino E, Ali M, Inglehearn CF (2019) Matrix metalloproteinases in keratoconus—too much of a good thing? Exp Eye Res 182:137–143

    Article  PubMed  Google Scholar 

  16. Hasby EA, Saad HA (2013) Immunohistochemical expression of Fas ligand (FasL) and neprilysin (neutral endopeptidase/CD10) in keratoconus. Int Ophthalmol 33(2):125–131

    Article  PubMed  Google Scholar 

  17. Elbeyli A, Kurtul BE (2021) Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio levels are associated with keratoconus. Indian J Ophthalmol 69(7):1725–1729

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hazra S, Chaudhuri AG, Tiwary BK, Chakrabarti N (2022) Integrated network-based multiple computational analyses for identification of co-expressed candidate genes associated with neurological manifestations of COVID-19. Sci Rep 12(1):17141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hao XD, Gao H, Xu WH, Shan C, Liu Y, Zhou ZX et al (2021) Systematically displaying the pathogenesis of keratoconus via multi-level related gene enrichment-based review. Front Med 8:770138

    Article  Google Scholar 

  20. Hu D, Lin Z, Jiang J, Li P, Zhang Z, Yang C (2022) Identification of key genes and molecular pathways in keratoconus: integrating text mining and bioinformatics analysis. Biomed Res Int 2022:4740141

    Article  PubMed  PubMed Central  Google Scholar 

  21. Dou S, Wang Q, Zhang B, Wei C, Wang H, Liu T et al (2022) Single-cell atlas of keratoconus corneas revealed aberrant transcriptional signatures and implicated mechanical stretch as a trigger for keratoconus pathogenesis. Cell Discov 8(1):66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Arbab M, Tahir S, Niazi MK, Ishaq M, Hussain A, Siddique PM et al (2017) TNF-α genetic predisposition and higher expression of inflammatory pathway components in keratoconus. Invest Ophthalmol Vis Sci 58(9):3481–3487

    Article  CAS  PubMed  Google Scholar 

  23. Xu X, Zhang X, Cui Y, Yang H, ** X, Wu J et al (2020) Three novel variants identified within ECM-related genes in Chinese Han keratoconus patients. Sci Rep 10(1):5844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bykhovskaya Y, Gromova A, Makarenkova HP, Rabinowitz YS (2016) Abnormal regulation of extracellular matrix and adhesion molecules in corneas of patients with keratoconus. Int J Keratoconus Ectatic Corneal Dis 5(2):63–70

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chiambaretta F, Nakamura H, De Graeve F, Sakai H, Marceau G, Maruyama Y et al (2006) Kruppel-like factor 6 (KLF6) affects the promoter activity of the alpha1-proteinase inhibitor gene. Invest Ophthalmol Vis Sci 47(2):582–590

    Article  PubMed  Google Scholar 

  26. Chung ES, Lee KH, Kim M, Chang EJ, Chung TY, Kim EK et al (2013) Expression of neurotrophic factors and their receptors in keratoconic cornea. Curr Eye Res 38(7):743–750

    Article  CAS  PubMed  Google Scholar 

  27. Engler C, Chakravarti S, Doyle J, Eberhart CG, Meng H, Stark WJ et al (2011) Transforming growth factor-β signaling pathway activation in Keratoconus. Am J Ophthalmol 151(5):752–9.e2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hao XD, Chen ZL, Qu ML, Zhao XW, Li SX, Chen P (2016) Decreased integrity, content, and increased transcript level of mitochondrial DNA are associated with keratoconus. PLoS ONE 11(10):e0165580

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kenney MC, Chwa M, Atilano SR, Tran A, Carballo M, Saghizadeh M et al (2005) Increased levels of catalase and cathepsin V/L2 but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays a role in this disorder. Invest Ophthalmol Vis Sci 46(3):823–832

    Article  PubMed  Google Scholar 

  30. Khaled ML, Bykhovskaya Y, Yablonski SER, Li H, Drewry MD, Aboobakar IF et al (2018) Differential expression of coding and long noncoding RNAs in keratoconus-affected corneas. Invest Ophthalmol Vis Sci 59(7):2717–2728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Macé M, Galiacy SD, Erraud A, Mejía JE, Etchevers H, Allouche M et al (2011) Comparative transcriptome and network biology analyses demonstrate antiproliferative and hyperapoptotic phenotypes in human keratoconus corneas. Invest Ophthalmol Vis Sci 52(9):6181–6191

    Article  PubMed  Google Scholar 

  32. Kabza M, Karolak JA, Rydzanicz M, Szcześniak MW, Nowak DM, Ginter-Matuszewska B et al (2017) Collagen synthesis disruption and downregulation of core elements of TGF-β, Hippo, and Wnt pathways in keratoconus corneas. Eur J Hum Genet EJHG 25(5):582–590

    Article  CAS  PubMed  Google Scholar 

  33. Rabinowitz YS, Dong L, Wistow G (2005) Gene expression profile studies of human keratoconus cornea for NEIBank: a novel cornea-expressed gene and the absence of transcripts for aquaporin 5. Invest Ophthalmol Vis Sci 46(4):1239–1246

    Article  PubMed  Google Scholar 

  34. Saghizadeh M, Chwa M, Aoki A, Lin B, Pirouzmanesh A, Brown DJ et al (2001) Altered expression of growth factors and cytokines in keratoconus, bullous keratopathy and diabetic human corneas. Exp Eye Res 73(2):179–189

    Article  CAS  PubMed  Google Scholar 

  35. Shinde V, Hu N, Mahale A, Maiti G, Daoud Y, Eberhart CG et al (2020) RNA sequencing of corneas from two keratoconus patient groups identifies potential biomarkers and decreased NRF2-antioxidant responses. Sci Rep 10(1):9907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang YN, Liu XN, Wang XD, Yin Y, Chen Y, **ao XH et al (2019) Expression of visual system homeobox 1 in human keratoconus. Int J Ophthalmol 12(2):201–206

    PubMed  PubMed Central  Google Scholar 

  37. Whitelock RB, Fukuchi T, Zhou L, Twining SS, Sugar J, Feder RS et al (1997) Cathepsin G, acid phosphatase, and alpha 1-proteinase inhibitor messenger RNA levels in keratoconus corneas. Invest Ophthalmol Vis Sci 38(2):529–534

    CAS  PubMed  Google Scholar 

  38. Zhao G, Wang C, Sun W, Zhang W, Li Y, Sheng H et al (2002) The expression of protein betaig-h3 inducible by transforming growth factor-beta in keratoconus and normal cornea. Chin J Ophthalmol 38(7):419–421

    Google Scholar 

  39. Nowak-Malczewska DM, Karolak JA, Swierkowska J, Jaworska MM, Kulinska KI, Polakowski P et al (2021) Changes in nuclear gene expression related to mitochondrial function affect extracellular matrix, collagens, and focal adhesion in keratoconus. Transl Vis Sci Technol 10(11):6

    Article  PubMed  PubMed Central  Google Scholar 

  40. Karolak JA, Ginter-Matuszewska B, Tomela K, Kabza M, Nowak-Malczewska DM, Rydzanicz M et al (2020) Further evaluation of differential expression of keratoconus candidate genes in human corneas. PeerJ 8:e9793

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sarker-Nag A, Hutcheon AE, Karamichos D (2016) Mitochondrial profile and responses to TGF-β ligands in keratoconus. Curr Eye Res 41(7):900–907

    Article  CAS  PubMed  Google Scholar 

  42. Atilano SR, Lee DH, Fukuhara PS, Chwa M, Nesburn AB, Udar N et al (2019) Corneal oxidative damage in keratoconus cells due to decreased oxidant elimination from modified expression levels of SOD enzymes, PRDX6, SCARA3, CPSF3, and FOXM1. J Ophthalmic Vis Res 14(1):62–70

    Article  PubMed  PubMed Central  Google Scholar 

  43. Chiplunkar S, Chamblis K, Chwa M, Rosenberg S, Kenney MC, Brown DJ (1999) Enhanced expression of a transmembrane phosphotyrosine phosphatase (LAR) in keratoconus cultures and corneas. Exp Eye Res 68(3):283–293

    Article  CAS  PubMed  Google Scholar 

  44. Du G, Liu C, Li X, Chen W, He R, Wang X et al (2016) Induction of matrix metalloproteinase-1 by tumor necrosis factor-α is mediated by interleukin-6 in cultured fibroblasts of keratoconus. Exp Biol Med (Maywood) 241(18):2033–2041

    Article  CAS  PubMed  Google Scholar 

  45. García B, García-Suárez O, Merayo-Lloves J, Alcalde I, Alfonso JF, Fernández-Vega Cueto L et al (2016) Differential expression of proteoglycans by corneal stromal cells in keratoconus. Invest Ophthalmol Vis Sci 57(6):2618–2628

    Article  PubMed  Google Scholar 

  46. García B, García-Suárez O, Merayo-Lloves J, Ferrara G, Alcalde I, González J et al (2017) Heparanase overexpresses in keratoconic cornea and tears depending on the pathologic grade. Dis Markers 2017:3502386

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ha NT, Nakayasu K, Murakami A, Ishidoh K, Kanai A (2004) Microarray analysis identified differentially expressed genes in keratocytes from keratoconus patients. Curr Eye Res 28(6):373–379

    Article  CAS  PubMed  Google Scholar 

  48. Joseph R, Srivastava OP, Pfister RR (2012) Downregulation of β-actin gene and human antigen R in human keratoconus. Invest Ophthalmol Vis Sci 53(7):4032–4041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lee JE, Oum BS, Choi HY, Lee SU, Lee JS (2009) Evaluation of differentially expressed genes identified in keratoconus. Mol Vis 15:2480–2487

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mootha VV, Kanoff JM, Shankardas J, Dimitrijevich S (2009) Marked reduction of alcohol dehydrogenase in keratoconus corneal fibroblasts. Mol Vis 15:706–712

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Peters DP, Harrison DA, Brandt CR (1993) Heterogeneity of type I collagen expression in human corneal keratoconus fibroblasts. Ophthalmic Res 25(5):273–279

    Article  CAS  PubMed  Google Scholar 

  52. Priyadarsini S, McKay TB, Sarker-Nag A, Karamichos D (2015) Keratoconus in vitro and the key players of the TGF-β pathway. Mol Vis 21:577–588

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Saee-Rad S, Raoofian R, Mahbod M, Miraftab M, Mojarrad M, Asgari S et al (2013) Analysis of superoxide dismutase 1, dual-specificity phosphatase 1, and transforming growth factor, beta 1 genes expression in keratoconic and non-keratoconic corneas. Mol Vis 19:2501–2507

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Sharif R, Khaled ML, McKay TB, Liu Y, Karamichos D (2019) Transcriptional profiling of corneal stromal cells derived from patients with keratoconus. Sci Rep 9(1):12567

    Article  PubMed  PubMed Central  Google Scholar 

  55. Wentz-Hunter K, Cheng EL, Ueda J, Sugar J, Yue BY (2001) Keratocan expression is increased in the stroma of keratoconus corneas. Mol Med (Cambridge, Mass) 7(7):470–477

    Article  CAS  Google Scholar 

  56. Stachon T, Nastaranpour M, Seitz B, Meese E, Latta L, Taneri S et al (2022) Altered regulation of mRNA and miRNA expression in epithelial and stromal tissue of keratoconus corneas. Invest Ophthalmol Vis Sci 63(8):7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ayan B, Yuksel N, Carhan A, Gumuşkaya Ocal B, Akcay E, Cagil N et al (2019) Evaluation estrogen, progesteron and androgen receptor expressions in corneal epithelium in keratoconus. Contact Lens Anterior Eye 42(5):492–496

    Article  PubMed  Google Scholar 

  58. Nielsen K, Birkenkamp-Demtröder K, Ehlers N, Orntoft TF (2003) Identification of differentially expressed genes in keratoconus epithelium analyzed on microarrays. Invest Ophthalmol Vis Sci 44(6):2466–2476

    Article  PubMed  Google Scholar 

  59. Pahuja N, Kumar NR, Shroff R, Shetty R, Nuijts RM, Ghosh A et al (2016) Differential molecular expression of extracellular matrix and inflammatory genes at the corneal cone apex drives focal weakening in keratoconus. Invest Ophthalmol Vis Sci 57(13):5372–5382

    Article  CAS  PubMed  Google Scholar 

  60. Shetty R, Sharma A, Pahuja N, Chevour P, Padmajan N, Dhamodaran K et al (2017) Oxidative stress induces dysregulated autophagy in corneal epithelium of keratoconus patients. PLoS ONE 12(9):e0184628

    Article  PubMed  PubMed Central  Google Scholar 

  61. Shetty R, Sathyanarayanamoorthy A, Ramachandra RA, Arora V, Ghosh A, Srivatsa PR et al (2015) Attenuation of lysyl oxidase and collagen gene expression in keratoconus patient corneal epithelium corresponds to disease severity. Mol Vis 21:12–25

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Shetty R, Vunnava KP, Dhamodaran K, Matalia H, Murali S, Jayadev C et al (2019) Characterization of corneal epithelial cells in keratoconus. Transl Vis Sci Technol 8(1):2

    Article  PubMed  PubMed Central  Google Scholar 

  63. Sutton G, Madigan M, Roufas A, McAvoy J (2010) Secreted frizzled-related protein 1 (SFRP1) is highly upregulated in keratoconus epithelium: a novel finding highlighting a new potential focus for keratoconus research and treatment. Clin Exp Ophthalmol 38(1):43–48

    Article  PubMed  Google Scholar 

  64. You J, Corley SM, Wen L, Hodge C, Höllhumer R, Madigan MC et al (2018) RNA-Seq analysis and comparison of corneal epithelium in keratoconus and myopia patients. Sci Rep 8(1):389

    Article  PubMed  PubMed Central  Google Scholar 

  65. Foster JW, Parikh RN, Wang J, Bower KS, Matthaei M, Chakravarti S et al (2021) Transcriptomic and immunohistochemical analysis of progressive keratoconus reveal altered WNT10A in epithelium and Bowman’s layer. Invest Ophthalmol Vis Sci 62(6):16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Shetty R, Ghosh A, Lim RR, Subramani M, Mihir K, Reshma AR et al (2015) Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. Invest Ophthalmol Vis Sci 56(2):738–750

    Article  CAS  PubMed  Google Scholar 

  67. Sun X, Zhang H, Shan M, Dong Y, Zhang L, Chen L et al (2022) Comprehensive transcriptome analysis of patients with keratoconus highlights the regulation of immune responses and inflammatory processes. Front Genet 13:782709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Regueiro U, López-López M, Hervella P, Sobrino T, Lema I 2021 Corneal and conjunctival alteration of innate immune expression in first-degree relatives of keratoconus patients. Graefe's Arch Clin Exp Ophthalmol 259(2):459–67.

  69. Lupasco T, He Z, Cassagne M, Sagnial T, Brion L, Fournié P et al (2022) Corneal epithelium in keratoconus underexpresses active NRF2 and a subset of oxidative stress-related genes. PLoS ONE 17(10):e0273807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Navel V, Malecaze J, Belville C, Choltus H, Henrioux F, Dutheil F et al (2022) Dysregulation of receptor for advanced glycation end products (RAGE) expression as a biomarker of keratoconus. Dis Markers 2022:1543742

    Article  PubMed  PubMed Central  Google Scholar 

  71. Yıldız E, Aydemir D, Zibandeh N, Kuşan E, Gümüş K, İlhan Saraç Ö et al (2022) Investigation of mitophagy biomarkers in corneal epithelium of keratoconus patients. Curr Eye Res 47(5):661–669

    Article  PubMed  Google Scholar 

  72. Mas Tur V, MacGregor C, Jayaswal R, O’Brart D, Maycock N (2017) A review of keratoconus: diagnosis, pathophysiology, and genetics. Surv Ophthalmol 62(6):770–783

    Article  PubMed  Google Scholar 

  73. Bykhovskaya Y, Rabinowitz YS (2021) Update on the genetics of keratoconus. Exp Eye Res 202:108398

    Article  CAS  PubMed  Google Scholar 

  74. Lucas SEM, Burdon KP (2020) Genetic and environmental risk factors for keratoconus. Ann Rev Vis Sci 6:25–46

    Article  Google Scholar 

  75. Bykhovskaya Y, Li X, Taylor KD, Haritunians T, Rotter JI, Rabinowitz YS (2016) Linkage analysis of high-density SNPs confirms keratoconus locus at 5q chromosomal region. Ophthalmic Genet 37(1):109–110

    PubMed  Google Scholar 

  76. Bisceglia L, De Bonis P, Pizzicoli C, Fischetti L, Laborante A, Di Perna M et al (2009) Linkage analysis in keratoconus: replication of locus 5q21.2 and identification of other suggestive Loci. Investig Ophthalmol Vis Sci 50(3):1081–1086

    Article  Google Scholar 

  77. He W, Han X, Ong JS, Hewitt AW, Mackey DA, Gharahkhani P et al (2022) Association of novel loci with keratoconus susceptibility in a multitrait genome-wide association study of the UK Biobank database and Canadian longitudinal study on aging. JAMA Ophthalmol 140(6):568–576

    Article  PubMed  PubMed Central  Google Scholar 

  78. Hardcastle AJ, Liskova P, Bykhovskaya Y, McComish BJ, Davidson AE, Inglehearn CF et al (2021) A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus. Commun Biol 4(1):266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Xu L, Yang K, Fan Q, Zhao D, Pang C, Ren S (2021) Whole mitochondrial genome analysis in Chinese patients with keratoconus. Mol Vis 27:270–282

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Guan T, Wang X, Zheng LB, Wu HJ, Yao YF (2017) Analysis of the VSX1 gene in sporadic keratoconus patients from China. BMC Ophthalmol 17(1):173

    Article  PubMed  PubMed Central  Google Scholar 

  81. Jurkiewicz T, Marty AS (2021) Correlation between keratoconus and pollution. Ophthalmic Epidemiol 28(6):495–501

    Article  CAS  PubMed  Google Scholar 

  82. Ferrari G, Rama P (2020) The keratoconus enigma: A review with emphasis on pathogenesis. Ocul Surf 18(3):363–373

    Article  PubMed  Google Scholar 

  83. Gu C, Wu L, Li X (2013) IL-17 family: cytokines, receptors and signaling. Cytokine 64(2):477–485

    Article  CAS  PubMed  Google Scholar 

  84. Maertzdorf J, Osterhaus AD, Verjans GM (2002) IL-17 expression in human herpetic stromal keratitis: modulatory effects on chemokine production by corneal fibroblasts. J Immunol (Baltimore, Md: 1950) 169(10):5897–5903

    Article  CAS  Google Scholar 

  85. Hong JW, Liu JJ, Lee JS, Mohan RR, Mohan RR, Woods DJ et al (2001) Proinflammatory chemokine induction in keratocytes and inflammatory cell infiltration into the cornea. Invest Ophthalmol Vis Sci 42(12):2795–2803

    CAS  PubMed  Google Scholar 

  86. Hou A, Tong L (2018) Expression, regulation, and effects of Interleukin-17f in the human ocular surface. Ocul Immunol Inflamm 26(7):1069–1077

    Article  CAS  PubMed  Google Scholar 

  87. Wojcik KA, Blasiak J, Szaflik J, Szaflik JP (2014) Role of biochemical factors in the pathogenesis of keratoconus. Acta Biochim Pol 61(1):55–62

    Article  PubMed  Google Scholar 

  88. Ionescu C, Corbu CG, Tanase C, Jonescu-Cuypers C, Nicula C, Dascalescu D et al (2016) Inflammatory biomarkers profile as microenvironmental expression in keratoconus. Dis Markers 2016:1243819

    Article  PubMed  PubMed Central  Google Scholar 

  89. Karolak JA, Gambin T, Pitarque JA, Molinari A, Jhangiani S, Stankiewicz P et al (2017) Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1-q35.3 susceptibility locus identified by whole-exome sequencing. Eur J Hum Genet 25(1):73–78

    Article  CAS  PubMed  Google Scholar 

  90. Gomes IB, Ayo CM, Lopes AG, Kumano LS, de Faria Junior GM, de Almeida Jr GC et al (2021) Mol Biol Rep 48(11):7165–7170

    Article  CAS  PubMed  Google Scholar 

  91. Annibaldi A, Meier P (2018) Checkpoints in TNF-induced cell death: implications in inflammation and cancer. Trends Mol Med 24(1):49–65

    Article  CAS  PubMed  Google Scholar 

  92. Taft J, Markson M, Legarda D, Patel R, Chan M, Malle L et al (2021) Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death. Cell 184(17):4447–63.e20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhou L, Zhou W, Joseph AM, Chu C, Putzel GG, Fang B et al (2022) Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation. Nat Immunol 23(2):251–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lema I, Durán JA (2005) Inflammatory molecules in the tears of patients with keratoconus. Ophthalmology 112(4):654–659

    Article  PubMed  Google Scholar 

  95. Duran JA, Lema I (2003) Inflammatory markers in keratoconus. Investig Ophthalmol Vis Sci 44(13):1314

    Google Scholar 

  96. Jun AS, Cope L, Speck C, Feng X, Lee S, Meng H et al (2011) Subnormal cytokine profile in the tear fluid of keratoconus patients. PLoS ONE 6(1):e16437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Peyman A, Namgar M, Feizi A, Hakemi MG, Nasab FH, Pourazizi M (2021) Interleukin-6 and tumor necrosis factor-α levels in tear film of Keratoconus patients. J Res Med Sci 26:75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cheung IM, McGhee CN, Sherwin T (2013) A new perspective on the pathobiology of keratoconus: interplay of stromal wound healing and reactive species-associated processes. Clin Exp Optom 96(2):188–196

    Article  PubMed  Google Scholar 

  99. Nakamura M, Nishida T (1999) Differential effects of epidermal growth factor and interleukin 6 on corneal epithelial cells and vascular endothelial cells. Cornea 18(4):452–458

    Article  CAS  PubMed  Google Scholar 

  100. Ebihara N, Matsuda A, Nakamura S, Matsuda H, Murakami A (2011) Role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing. Invest Ophthalmol Vis Sci 52(12):8549–8557

    Article  CAS  PubMed  Google Scholar 

  101. Kaldawy RM, Wagner J, Ching S, Seigel GM (2002) Evidence of apoptotic cell death in keratoconus. Cornea 21(2):206–209

    Article  PubMed  Google Scholar 

  102. Wilson SE, He YG, Weng J, Li Q, McDowall AW, Vital M et al (1996) Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin-1 system in the modulation of corneal tissue organization and wound healing. Exp Eye Res 62(4):325–327

    Article  CAS  PubMed  Google Scholar 

  103. Wilson SE, Li Q, Weng J, Barry-Lane PA, Jester JV, Liang Q et al (1996) The Fas-Fas ligand system and other modulators of apoptosis in the cornea. Invest Ophthalmol Vis Sci 37(8):1582–1592

    CAS  PubMed  Google Scholar 

  104. Moura GS, Santos A, Cenedeze MA, Hiyane MI, Camara NOS, Barbosa de Sousa L et al (2021) Increased lacrimal inflammatory mediators in patients with keratoconus. Mol Vis 27:656–665

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Garg P (2017) Altered tear inflammatory profile in Indian keratoconus patients. Indian J Ophthalmol 65(11):1073–1074

    Article  PubMed  PubMed Central  Google Scholar 

  106. Sugaya S, Sakimoto T, Shoji J, Sawa M (2011) Regulation of soluble interleukin-6 (IL-6) receptor release from corneal epithelial cells and its role in the ocular surface. Jpn J Ophthalmol 55(3):277–282

    Article  CAS  PubMed  Google Scholar 

  107. Smith VA, Rishmawi H, Hussein H, Easty DL (2001) Tear film MMP accumulation and corneal disease. Br J Ophthalmol 85(2):147–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hulkkonen J, Pertovaara M, Antonen J, Pasternack A, Hurme M, Pöllänen P et al (2004) Matrix metalloproteinase 9 (MMP-9) gene polymorphism and MMP-9 plasma levels in primary Sjogren’s syndrome. Rheumatology (Oxford) 43(12):1476–1479

    Article  CAS  PubMed  Google Scholar 

  109. Mutlu M, Sarac O, Cağıl N, Avcıoğlu G (2020) Relationship between tear eotaxin-2 and MMP-9 with ocular allergy and corneal topography in keratoconus patients. Int Ophthalmol 40(1):51–57

    Article  PubMed  Google Scholar 

  110. Li DQ, Lokeshwar BL, Solomon A, Monroy D, Ji Z, Pflugfelder SC (2001) Regulation of MMP-9 production by human corneal epithelial cells. Exp Eye Res 73(4):449–459

    Article  CAS  PubMed  Google Scholar 

  111. Balasubramanian SA, Mohan S, Pye DC, Willcox MD (2012) Proteases, proteolysis and inflammatory molecules in the tears of people with keratoconus. Acta Ophthalmol 90(4):e303–e309

    Article  PubMed  Google Scholar 

  112. Cui N, Hu M, Khalil RA (2017) Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci 147:1–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zilfyan A, Abovyan A (2017) A new approach to keratoconus diagnostics using matrix metalloproteinase-9 marker. Georgian Med News 270:20–24

    Google Scholar 

  114. Sobrino T, Regueiro U, Malfeito M, Vieites-Prado A, Pérez-Mato M, Campos F et al (2017) Higher expression of toll-like receptors 2 and 4 in blood cells of keratoconus patiens. Sci Rep 7(1):12975

    Article  PubMed  PubMed Central  Google Scholar 

  115. Lema I, Sobrino T, Durán JA, Brea D, Díez-Feijoo E (2009) Subclinical keratoconus and inflammatory molecules from tears. Br J Ophthalmol 93(6):820–824

    Article  CAS  PubMed  Google Scholar 

  116. Daphne Teh AL, Jayapalan JJ, Loke MF, Wan Abdul Kadir AJ, Subrayan V (2021) Identification of potential serum metabolic biomarkers for patient with keratoconus using untargeted metabolomics approach. Exp Eye Res 211:108734

    Article  CAS  PubMed  Google Scholar 

  117. McKay TB, Priyadarsini S, Karamichos D (2022) Sex hormones, growth hormone, and the cornea. Cells 11(2):224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Suzuki T, Kinoshita Y, Tachibana M, Matsushima Y, Kobayashi Y, Adachi W et al (2001) Expression of sex steroid hormone receptors in human cornea. Curr Eye Res 22(1):28–33

    Article  CAS  PubMed  Google Scholar 

  119. Escandon P, Nicholas SE, Cunningham RL, Murphy DA, Riaz KM, Karamichos D (2022) The role of estriol and estrone in keratoconic stromal sex hormone receptors. Int J Mol Sci 23(2):916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Karamichos D, Escandon P, Vasini B, Nicholas SE, Van L, Dang DH et al (2022) Anterior pituitary, sex hormones, and keratoconus: beyond traditional targets. Prog Retin Eye Res 88:101016

    Article  CAS  PubMed  Google Scholar 

  121. Zhao X, Yuan Y, Sun T, Zhang Y, Chen Y (2022) Associations between keratoconus and the level of sex hormones: a cross-sectional study. Front Med 9:828233

    Article  Google Scholar 

  122. Fink BA, Sinnott LT, Wagner H, Friedman C, Zadnik K (2010) The influence of gender and hormone status on the severity and progression of keratoconus. Cornea 29(1):65–72

    Article  PubMed  Google Scholar 

  123. McKay TB, Hjortdal J, Sejersen H, Karamichos D (2017) Differential effects of hormones on cellular metabolism in keratoconus in vitro. Sci Rep 7:42896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Henan Eye Hospital, Henan Provincial People’s Hospital/People’s Hospital of Zhengzhou University, Zhengzhou, 450003, China

    Feiying Meng & Shengwei Ren

  2. Eye Institute, Henan Academy of Innovations in Medical Science, Zhengzhou, China

    Feiying Meng & Shengwei Ren

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  1. Feiying Meng
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MFY conceived and designed the study. MFY and RSW performed the literature search and data extraction. MFY and RSW drafted the manuscript. All authors read and approved the final manuscript.

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Meng, F., Ren, S. Identification of hub genes and molecular pathways in keratoconus by integrating bioinformatics and literature mining at the RNA level. Int Ophthalmol 44, 244 (2024). https://doi.org/10.1007/s10792-024-03071-3

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