Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWBTED2)

• DOT Name: Collagen alpha-1(VIII) chain (COL8A1)
• Synonyms: Endothelial collagen
• Gene Name: COL8A1
• Related Disease:
  Age-related macular degeneration
  Breast carcinoma
  Corneal dystrophy
  Diabetic kidney disease
  Focal segmental glomerulosclerosis
  Fuchs' endothelial dystrophy
  High blood pressure
  Isolated cleft lip
  Keratoconus
  Megalocornea
  Myopia
  Neovascular age-related macular degeneration
  Tourette syndrome
  Retinopathy
  Colon adenocarcinoma
  Glycogen storage disease type II
  Non-insulin dependent diabetes
  OPTN-related open angle glaucoma
• UniProt ID: CO8A1_HUMAN
• Pfam ID: PF00386 ; PF01391
• Sequence:
  MAVLPGPLQLLGVLLTISLSSIRLIQAGAYYGIKPLPPQIPPQMPPQIPQYQPLGQQVPH
  MPLAKDGLAMGKEMPHLQYGKEYPHLPQYMKEIQPAPRMGKEAVPKKGKEIPLASLRGEQ
  GPRGEPGPRGPPGPPGLPGHGIPGIKGKPGPQGYPGVGKPGMPGMPGKPGAMGMPGAKGE
  IGQKGEIGPMGIPGPQGPPGPHGLPGIGKPGGPGLPGQPGPKGDRGPKGLPGPQGLRGPK
  GDKGFGMPGAPGVKGPPGMHGPPGPVGLPGVGKPGVTGFPGPQGPLGKPGAPGEPGPQGP
  IGVPGVQGPPGIPGIGKPGQDGIPGQPGFPGGKGEQGLPGLPGPPGLPGIGKPGFPGPKG
  DRGMGGVPGALGPRGEKGPIGAPGIGGPPGEPGLPGIPGPMGPPGAIGFPGPKGEGGIVG
  PQGPPGPKGEPGLQGFPGKPGFLGEVGPPGMRGLPGPIGPKGEAGQKGVPGLPGVPGLLG
  PKGEPGIPGDQGLQGPPGIPGIGGPSGPIGPPGIPGPKGEPGLPGPPGFPGIGKPGVAGL
  HGPPGKPGALGPQGQPGLPGPPGPPGPPGPPAVMPPTPPPQGEYLPDMGLGIDGVKPPHA
  YGAKKGKNGGPAYEMPAFTAELTAPFPPVGAPVKFNKLLYNGRQNYNPQTGIFTCEVPGV
  YYFAYHVHCKGGNVWVALFKNNEPVMYTYDEYKKGFLDQASGSAVLLLRPGDRVFLQMPS
  EQAAGLYAGQYVHSSFSGYLLYPM
• Function: Macromolecular component of the subendothelium. Major component of the Descemet's membrane (basement membrane) of corneal endothelial cells. Also a component of the endothelia of blood vessels. Necessary for migration and proliferation of vascular smooth muscle cells and thus, has a potential role in the maintenance of vessel wall integrity and structure, in particular in atherogenesis; Vastatin, the C-terminal fragment comprising the NC1 domain, inhibits aortic endothelial cell proliferation and causes cell apoptosis.
• Tissue Specificity: Expressed primarily in the subendothelium of large blood vessels. Also expressed in arterioles and venules in muscle, heart, kidney, spleen, umbilical cord, liver and lung and is also found in connective tissue layers around hair follicles, around nerve bundles in muscle, in the dura of the optic nerve, in cornea and sclera, and in the perichondrium of cartilaginous tissues. In the kidney, expressed in mesangial cells, glomerular endothelial cells, and tubular epithelial cells. Also expressed in mast cells, and in astrocytes during the repair process. Expressed in Descemet's membrane. Specifically expressed in peritoneal fibroblasts and mesothelial cells.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  Integrin cell surface interactions (R-HSA-216083)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Corneal dystrophy	DISRDPA6	Strong	Genetic Variation	[3]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[4]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Altered Expression	[4]
Fuchs' endothelial dystrophy	DISL7TXC	Strong	Genetic Variation	[3]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[5]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[6]
Keratoconus	DISOONXH	Strong	Genetic Variation	[7]
Megalocornea	DISIMNF0	Strong	Genetic Variation	[7]
Myopia	DISK5S60	Strong	Genetic Variation	[5]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[8]
Tourette syndrome	DISX9D54	Strong	Genetic Variation	[9]
Retinopathy	DISB4B0F	moderate	Genetic Variation	[10]
Colon adenocarcinoma	DISDRE0J	Limited	Altered Expression	[11]
Glycogen storage disease type II	DISXZPBC	Limited	Genetic Variation	[12]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[13]
OPTN-related open angle glaucoma	DISDR98A	Limited	Biomarker	[14]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Collagen alpha-1(VIII) chain (COL8A1).	[15]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[22]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[26]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[28]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Collagen alpha-1(VIII) chain (COL8A1).	[29]

References

• [1] Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane.Ophthalmology. 2018 Sep;125(9):1433-1443. doi: 10.1016/j.ophtha.2018.03.040. Epub 2018 Apr 26.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] No pathogenic mutations identified in the COL8A1 and COL8A2 genes in familial Fuchs corneal dystrophy.Invest Ophthalmol Vis Sci. 2006 Sep;47(9):3787-90. doi: 10.1167/iovs.05-1635.
• [4] Collagen type VIII expression in human diabetic nephropathy.Eur J Clin Invest. 2007 Oct;37(10):767-73. doi: 10.1111/j.1365-2362.2007.01864.x.
• [5] Evaluation of 10 AMD Associated Polymorphisms as a Cause of Choroidal Neovascularization in Highly Myopic Eyes.PLoS One. 2016 Sep 19;11(9):e0162296. doi: 10.1371/journal.pone.0162296. eCollection 2016.
• [6] Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.Nat Commun. 2017 Feb 24;8:14364. doi: 10.1038/ncomms14364.
• [7] Keratoconus is not associated with mutations in COL8A1 and COL8A2.Cornea. 2007 Sep;26(8):963-5. doi: 10.1097/ICO.0b013e31811dfaf7.
• [8] A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
• [9] CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1.PLoS One. 2013;8(3):e59061. doi: 10.1371/journal.pone.0059061. Epub 2013 Mar 22.
• [10] Diabetes duration may modify the association between genetic variation in the glycoprotein Ia subunit of the platelet collagen receptor and risk of severe diabetic retinopathy: a working hypothesis.Thromb Haemost. 2003 Jan;89(1):142-8.
• [11] Co-expression Network Analysis Identified COL8A1 Is Associated with the Progression and Prognosis in Human Colon Adenocarcinoma.Dig Dis Sci. 2018 May;63(5):1219-1228. doi: 10.1007/s10620-018-4996-5. Epub 2018 Mar 1.
• [12] Towards the application of precision medicine in Age-Related Macular Degeneration.Prog Retin Eye Res. 2018 Mar;63:132-146. doi: 10.1016/j.preteyeres.2017.11.004. Epub 2017 Nov 29.
• [13] A replication study of 19 GWAS-validated type 2 diabetes at-risk variants in the Lebanese population.Diabetes Res Clin Pract. 2013 Nov;102(2):117-22. doi: 10.1016/j.diabres.2013.09.001. Epub 2013 Sep 14.
• [14] Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness.Mol Vis. 2010 Oct 29;16:2185-91.
• [15] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [16] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [17] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [18] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [23] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [24] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [25] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [26] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [27] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [28] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [29] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.