Details of Disease

General Information of Disease (ID: DISOONXH)

• Disease Name: Keratoconus
• Synonyms: KC; noninflammatory corneal thining; isolated keratoconus; keratoconus (disease); conical cornea; keratoconus
• Disease Class: 9A76-9A78: Corneal disease
• Definition: A degenerative, structural disorder of the eye, characterized by a cone-shaped protrusion of the cornea. It may lead to visual disturbances.
• Disease Hierarchy:
  DISYKSRF: Genetic disease
  DISTUIM1: Corneal disease
  DISOONXH: Keratoconus
• ICD Code:
  ICD-11: ICD-11: 9A78.50
  ICD-10: ICD-10: H18.6
  Expand ICD-11: '9A78.50
  Expand ICD-10: 'H18.6
• Disease Identifiers:
  MONDO ID: MONDO_0015486
  MESH ID: D007640
  UMLS CUI: C0022578
  MedGen ID: 44015
  HPO ID: HP:0000563
  Orphanet ID: 2335
  SNOMED CT ID: 65636009

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Preclinical Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Riboflavin; ultraviolet-A (UVA) irradiation	DMI8VH3	Application submitted	NA	[1]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 11 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
ALDH3A2	TTB6UM0	moderate	Biomarker	[2]
CNTF	TTGEM5Q	moderate	Biomarker	[3]
CTSV	TTSD9T1	moderate	Genetic Variation	[4]
DSG3	TTEO4P8	moderate	Altered Expression	[5]
HKDC1	TTVUI8G	moderate	Genetic Variation	[6]
HMOX2	TTWZRL4	moderate	Biomarker	[7]
KIF26B	TTQWICZ	moderate	Genetic Variation	[8]
FOXO1	TTLRVIA	Strong	Genetic Variation	[9]
LOX	TTQHNAM	Strong	Biomarker	[10]
MAP3K19	TTRHJA3	Strong	Genetic Variation	[11]
RXRA	TT6PEUO	Strong	Genetic Variation	[9]

This Disease Is Related to 3 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
ABCA6	DTLMZUF	moderate	Genetic Variation	[12]
SLC4A11	DTH2J1G	moderate	Genetic Variation	[13]
SLC7A2	DTWY9RT	Strong	Altered Expression	[14]

This Disease Is Related to 46 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
DOCK9	OT84H8AD	Limited	Autosomal dominant	[15]
ACP2	OTLPA1LJ	moderate	Altered Expression	[16]
ADAMTS17	OTCFITM9	moderate	Genetic Variation	[12]
ADAMTS8	OT2KFY1S	moderate	Genetic Variation	[12]
ANAPC1	OT2YY35L	moderate	Genetic Variation	[12]
CLC	OTYMYR85	moderate	Altered Expression	[5]
COL6A1	OTYKSCOB	moderate	Genetic Variation	[12]
EMP3	OTODMJ1D	moderate	Altered Expression	[5]
GALNT14	OT9BSDDQ	moderate	Biomarker	[17]
GGTLC1	OTWJKUHQ	moderate	Biomarker	[18]
IPO5	OTAK40ED	moderate	Biomarker	[19]
KERA	OTAP9L2A	moderate	Altered Expression	[20]
KRT12	OTFOWNH2	moderate	Genetic Variation	[21]
KRT3	OT5U1Y8L	moderate	Biomarker	[22]
NAXD	OTPO2GM2	moderate	Biomarker	[23]
ND1	OTCLGIXV	moderate	Altered Expression	[24]
NEIL1	OTHBU5DJ	moderate	Genetic Variation	[25]
PLLP	OTFGCB9U	moderate	Biomarker	[26]
PROB1	OTG6OQIP	moderate	Genetic Variation	[6]
S100A2	OTTGHJ1H	moderate	Altered Expression	[5]
SERINC3	OTQ1LAJ1	moderate	Biomarker	[27]
STATH	OTQHBHM9	moderate	Genetic Variation	[28]
STK24	OTGUHOIL	moderate	Biomarker	[19]
AIPL1	OT4VBD78	Strong	Biomarker	[29]
AQP5	OT77GBY8	Strong	Altered Expression	[30]
BANP	OT1JMTBD	Strong	Genetic Variation	[9]
CAST	OTBXZZGF	Strong	Biomarker	[31]
COL5A1	OT24078H	Strong	Genetic Variation	[9]
COL8A1	OTWBTED2	Strong	Genetic Variation	[32]
COL8A2	OTASWJ69	Strong	Genetic Variation	[33]
CRB1	OTXYUNG0	Strong	Biomarker	[29]
CST4	OTXXM8EH	Strong	Biomarker	[34]
FNDC3B	OTBILGDR	Strong	Genetic Variation	[9]
KLF6	OTQY9S7F	Strong	Altered Expression	[35]
LIG3	OT48SKET	Strong	Genetic Variation	[36]
MPDZ	OT9WY1QM	Strong	Genetic Variation	[37]
PIP	OTH719AH	Strong	Altered Expression	[38]
PLK3	OT19CT2Z	Strong	Biomarker	[39]
PLXNA2	OTNNBJMQ	Strong	Biomarker	[40]
PPRC1	OT6GB3WR	Strong	Biomarker	[41]
PRDM5	OTU1GB68	Strong	Genetic Variation	[42]
RAB3GAP1	OT4DQ8F2	Strong	Genetic Variation	[9]
ROBO3	OTPVG40S	Strong	Genetic Variation	[43]
SFTPA1	OT87XL1U	Strong	Genetic Variation	[44]
TGFBI	OTR443C5	Strong	Genetic Variation	[21]
TIMP1	OTOXC51H	Strong	Altered Expression	[45]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Differential Expression of Coding and Long Noncoding RNAs in Keratoconus-Affected Corneas.Invest Ophthalmol Vis Sci. 2018 Jun 1;59(7):2717-2728. doi: 10.1167/iovs.18-24267.
• [3] Expression of neurotrophic factors and their receptors in keratoconic cornea.Curr Eye Res. 2013 Jul;38(7):743-50. doi: 10.3109/02713683.2013.774421. Epub 2013 Mar 14.
• [4] 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. 2005 Mar;46(3):823-32. doi: 10.1167/iovs.04-0549.
• [5] Altered expression of CLC, DSG3, EMP3, S100A2, and SLPI in corneal epithelium from keratoconus patients.Cornea. 2005 Aug;24(6):661-8. doi: 10.1097/01.ico.0000153556.59407.69.
• [6] Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1-q35.3 susceptibility locus identified by whole-exome sequencing.Eur J Hum Genet. 2017 Jan;25(1):73-78. doi: 10.1038/ejhg.2016.130. Epub 2016 Oct 5.
• [7] Investigation of Heme Oxygenase 2 Enzyme Protein Expression in Keratoconus and Normal Human Corneal Epithelium: An Immunohistochemical Study.Curr Eye Res. 2019 Jan;44(1):25-29. doi: 10.1080/02713683.2018.1521980. Epub 2018 Sep 19.
• [8] Association of KIF26B and COL4A4 gene polymorphisms with the risk of keratoconus in a sample of Iranian population.Int Ophthalmol. 2019 Nov;39(11):2621-2628. doi: 10.1007/s10792-019-01111-x. Epub 2019 May 10.
• [9] Evaluating the Association between Keratoconus and Reported Genetic Loci in a Han Chinese Population.Ophthalmic Genet. 2015 Jun;36(2):132-6. doi: 10.3109/13816810.2015.1005317. Epub 2015 Feb 12.
• [10] Mechanisms of Collagen Crosslinking in Diabetes and Keratoconus.Cells. 2019 Oct 11;8(10):1239. doi: 10.3390/cells8101239.
• [11] A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries.Hum Mol Genet. 2012 Jan 15;21(2):421-9. doi: 10.1093/hmg/ddr460. Epub 2011 Oct 6.
• [12] Genetic Variants Associated With Corneal Biomechanical Properties and Potentially Conferring Susceptibility to Keratoconus in a Genome-Wide Association Study.JAMA Ophthalmol. 2019 Sep 1;137(9):1005-1012. doi: 10.1001/jamaophthalmol.2019.2058.
• [13] Substitution at IL1RN and deletion at SLC4A11 segregating with phenotype in familial keratoconus.Invest Ophthalmol Vis Sci. 2013 Mar 1;54(3):2207-15. doi: 10.1167/iovs.13-11592.
• [14] Detection and regulation of cationic amino acid transporters in healthy and diseased ocular surface.Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1112-21. doi: 10.1167/iovs.08-2368. Epub 2008 Nov 7.
• [15] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [16] Cathepsin G, acid phosphatase, and alpha 1-proteinase inhibitor messenger RNA levels in keratoconus corneas.Invest Ophthalmol Vis Sci. 1997 Feb;38(2):529-34.
• [17] Autosomal Recessive Non-syndromic Keratoconus: Homozygous Frameshift Variant in the Candidate Novel Gene GALNT14.Curr Mol Med. 2019;19(9):683-687. doi: 10.2174/1566524019666190730095630.
• [18] Tear fluid small molecular antioxidants profiling shows lowered glutathione in keratoconus.Exp Eye Res. 2012 Oct;103:41-6. doi: 10.1016/j.exer.2012.07.010. Epub 2012 Aug 10.
• [19] Molecular Screening of Keratoconus Susceptibility Sequence Variants in VSX1, TGFBI, DOCK9, STK24, and IPO5 Genes in Polish Patients and Novel TGFBI Variant Identification.Ophthalmic Genet. 2016;37(1):37-43. doi: 10.3109/13816810.2014.926375. Epub 2014 Jun 18.
• [20] Keratocan expression is increased in the stroma of keratoconus corneas.Mol Med. 2001 Jul;7(7):470-7.
• [21] Mutation analysis of TGFBI and KRT12 in a case of concomitant keratoconus and granular corneal dystrophy.Graefes Arch Clin Exp Ophthalmol. 2017 Sep;255(9):1779-1786. doi: 10.1007/s00417-017-3699-5. Epub 2017 May 31.
• [22] Proteome profiling of corneal epithelium and identification of marker proteins for keratoconus, a pilot study.Exp Eye Res. 2006 Feb;82(2):201-9. doi: 10.1016/j.exer.2005.06.009. Epub 2005 Aug 3.
• [23] Comparative proteome analysis of the tear samples in patients with low-grade keratoconus.Int Ophthalmol. 2018 Oct;38(5):1895-1905. doi: 10.1007/s10792-017-0672-6. Epub 2017 Aug 7.
• [24] Decreased Integrity, Content, and Increased Transcript Level of Mitochondrial DNA Are Associated with Keratoconus.PLoS One. 2016 Oct 26;11(10):e0165580. doi: 10.1371/journal.pone.0165580. eCollection 2016.
• [25] Polymorphism of the DNA base excision repair genes in keratoconus.Int J Mol Sci. 2014 Oct 29;15(11):19682-99. doi: 10.3390/ijms151119682.
• [26] RNA-Seq analysis and comparison of corneal epithelium in keratoconus and myopia patients.Sci Rep. 2018 Jan 10;8(1):389. doi: 10.1038/s41598-017-18480-x.
• [27] Genetic epidemiological study of keratoconus: evidence for major gene determination.Am J Med Genet. 2000 Aug 28;93(5):403-9.
• [28] Mutation analysis of VSX1 and SOD1 in Iranian patients with keratoconus.Mol Vis. 2011;17:3128-36. Epub 2011 Nov 30.
• [29] Leber Congenital Amaurosis.Adv Exp Med Biol. 2018;1085:131-137. doi: 10.1007/978-3-319-95046-4_26.
• [30] Comparative expression analysis of aquaporin-5 (AQP5) in keratoconic and healthy corneas.Mol Vis. 2008 Apr 25;14:756-61.
• [31] Evaluating the association between calpastatin (CAST) gene and keratoconus in the Han Chinese population.Gene. 2018 May 5;653:10-13. doi: 10.1016/j.gene.2018.02.016. Epub 2018 Feb 8.
• [32] Keratoconus is not associated with mutations in COL8A1 and COL8A2.Cornea. 2007 Sep;26(8):963-5. doi: 10.1097/ICO.0b013e31811dfaf7.
• [33] Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype-phenotype correlation.Invest Ophthalmol Vis Sci. 2013 May 3;54(5):3215-23. doi: 10.1167/iovs.13-11781.
• [34] Changes in tear biomarker levels in keratoconus after corneal collagen crosslinking.Mol Vis. 2019 Jan 20;25:12-21. eCollection 2019.
• [35] Expression of Sp1 and KLF6 in the developing human cornea.Mol Vis. 2007 Aug 27;13:1451-7.
• [36] Polymorphism of the LIG3 gene in keratoconus and Fuchs endothelial corneal dystrophy.Cell Mol Biol (Noisy-le-grand). 2015 Mar 28;61(1):56-63.
• [37] Analysis of multiple genetic loci reveals MPDZ-NF1B rs1324183 as a putative genetic marker for keratoconus.Br J Ophthalmol. 2018 Dec;102(12):1736-1741. doi: 10.1136/bjophthalmol-2018-312218. Epub 2018 Jul 12.
• [38] Prolactin-Induced Protein is a novel biomarker for Keratoconus.Exp Eye Res. 2019 Feb;179:55-63. doi: 10.1016/j.exer.2018.10.015. Epub 2018 Oct 26.
• [39] Ten-Year Outcomes of Progressive Keratoconus Management With the Athens Protocol (Topography-Guided Partial-Refraction PRK Combined With CXL).J Refract Surg. 2019 Aug 1;35(8):478-483. doi: 10.3928/1081597X-20190627-01.
• [40] Bowman's topography for improved detection of early ectasia.J Biophotonics. 2019 Oct;12(10):e201900126. doi: 10.1002/jbio.201900126. Epub 2019 Jun 27.
• [41] Keratoconus after 40years of age: a longitudinal comparative population-based study.Int Ophthalmol. 2020 Mar;40(3):583-589. doi: 10.1007/s10792-019-01216-3. Epub 2019 Nov 7.
• [42] Whole exome sequencing identifies a heterozygous missense variant in the PRDM5 gene in a family with Axenfeld-Rieger syndrome.Neurogenetics. 2016 Jan;17(1):17-23. doi: 10.1007/s10048-015-0462-0. Epub 2015 Oct 21.
• [43] Horizontal Gaze Palsy With Progressive Scoliosis and Severe Keratoconus With a Compound Heterozygous Mutation in ROBO3.J Pediatr Ophthalmol Strabismus. 2014 May 28;51 Online:e29-32. doi: 10.3928/01913913-20140521-01.
• [44] Repeatability and comparison of new Corvis ST parameters in normal and keratoconus eyes.Sci Rep. 2019 Oct 25;9(1):15379. doi: 10.1038/s41598-019-51502-4.
• [45] Role of extracellular matrix remodelling gene SNPs in keratoconus.Br J Biomed Sci. 2020 Jan;77(1):13-18. doi: 10.1080/09674845.2019.1654346. Epub 2019 Aug 29.