Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLGV5SV)

• DOT Name: Protein CLEC16A (CLEC16A)
• Synonyms: C-type lectin domain family 16 member A
• Gene Name: CLEC16A
• Related Disease:
  Chronic kidney disease
  Classic Hodgkin lymphoma
  Acute coronary syndrome
  Alopecia areata
  Alzheimer disease
  Atopic dermatitis
  Autoimmune disease
  Behcet disease
  Coeliac disease
  Common variable immunodeficiency
  Crohn disease
  Eosinophilic esophagitis
  Immunodeficiency
  Juvenile idiopathic arthritis
  Multiple sclerosis
  Myocardial infarction
  Primary biliary cholangitis
  Sclerosing cholangitis
  Systemic lupus erythematosus
  Type-1 diabetes
  Allergic rhinitis
  Asthma
  High blood pressure
  Immune system disorder
  Primary adrenal insufficiency
  Addison disease
  Ankylosing spondylitis
  Psoriasis
  Seasonal allergic rhinitis
  Ulcerative colitis
  Schizophrenia
• UniProt ID: CL16A_HUMAN
• Pfam ID: PF19439 ; PF09758
• Sequence:
  MFGRSRSWVGGGHGKTSRNIHSLDHLKYLYHVLTKNTTVTEQNRNLLVETIRSITEILIW
  GDQNDSSVFDFFLEKNMFVFFLNILRQKSGRYVCVQLLQTLNILFENISHETSLYYLLSN
  NYVNSIIVHKFDFSDEEIMAYYISFLKTLSLKLNNHTVHFFYNEHTNDFALYTEAIKFFN
  HPESMVRIAVRTITLNVYKVSLDNQAMLHYIRDKTAVPYFSNLVWFIGSHVIELDDCVQT
  DEEHRNRGKLSDLVAEHLDHLHYLNDILIINCEFLNDVLTDHLLNRLFLPLYVYSLENQD
  KGGERPKISLPVSLYLLSQVFLIIHHAPLVNSLAEVILNGDLSEMYAKTEQDIQRSSAKP
  SIRCFIKPTETLERSLEMNKHKGKRRVQKRPNYKNVGEEEDEEKGPTEDAQEDAEKAKGT
  EGGSKGIKTSGESEEIEMVIMERSKLSELAASTSVQEQNTTDEEKSAAATCSESTQWSRP
  FLDMVYHALDSPDDDYHALFVLCLLYAMSHNKGMDPEKLERIQLPVPNAAEKTTYNHPLA
  ERLIRIMNNAAQPDGKIRLATLELSCLLLKQQVLMSAGCIMKDVHLACLEGAREESVHLV
  RHFYKGEDIFLDMFEDEYRSMTMKPMNVEYLMMDASILLPPTGTPLTGIDFVKRLPCGDV
  EKTRRAIRVFFMLRSLSLQLRGEPETQLPLTREEDLIKTDDVLDLNNSDLIACTVITKDG
  GMVQRFLAVDIYQMSLVEPDVSRLGWGVVKFAGLLQDMQVTGVEDDSRALNITIHKPASS
  PHSKPFPILQATFIFSDHIRCIIAKQRLAKGRIQARRMKMQRIAALLDLPIQPTTEVLGF
  GLGSSTSTQHLPFRFYDQGRRGSSDPTVQRSVFASVDKVPGFAVAQCINQHSSPSLSSQS
  PPSASGSPSGSGSTSHCDSGGTSSSSTPSTAQSPADAPMSPELPKPHLPDQLVIVNETEA
  DSKPSKNVARSAAVETASLSPSLVPARQPTISLLCEDTADTLSVESLTLVPPVDPHSLRS
  LTGMPPLSTPAAACTEPVGEEAACAEPVGTAED
• Function: Regulator of mitophagy through the upstream regulation of the RNF41/NRDP1-PRKN pathway. Mitophagy is a selective form of autophagy necessary for mitochondrial quality control. The RNF41/NRDP1-PRKN pathway regulates autophagosome-lysosome fusion during late mitophagy. May protect RNF41/NRDP1 from proteasomal degradation, RNF41/NRDP1 which regulates proteasomal degradation of PRKN. Plays a key role in beta cells functions by regulating mitophagy/autophagy and mitochondrial health.
• Tissue Specificity: Almost exclusively expressed in immune cells, including dendritic cells, B-lymphocytes and natural killer cells.

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Biomarker	[1]
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Genetic Variation	[2]
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[3]
Alopecia areata	DIS0XXBJ	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[6]
Autoimmune disease	DISORMTM	Strong	Biomarker	[7]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[8]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[9]
Common variable immunodeficiency	DISHE7JQ	Strong	Biomarker	[10]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[11]
Eosinophilic esophagitis	DISR8WSB	Strong	Genetic Variation	[12]
Immunodeficiency	DIS093I0	Strong	Biomarker	[10]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[13]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[14]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[15]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[16]
Sclerosing cholangitis	DIS7GZNB	Strong	Genetic Variation	[17]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[18]
Type-1 diabetes	DIS7HLUB	Strong	Biomarker	[7]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[19]
Asthma	DISW9QNS	moderate	Genetic Variation	[20]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[21]
Immune system disorder	DISAEGPH	moderate	Biomarker	[22]
Primary adrenal insufficiency	DISNMBYU	moderate	Genetic Variation	[23]
Addison disease	DIS7HNOH	Limited	Genetic Variation	[23]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[11]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[11]
Seasonal allergic rhinitis	DIS58KQX	Limited	Genetic Variation	[24]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[11]
Schizophrenia	DISSRV2N	No Known	Unknown	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Protein CLEC16A (CLEC16A).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein CLEC16A (CLEC16A).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein CLEC16A (CLEC16A).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein CLEC16A (CLEC16A).	[29]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein CLEC16A (CLEC16A).	[31]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein CLEC16A (CLEC16A).	[32]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein CLEC16A (CLEC16A).	[33]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Protein CLEC16A (CLEC16A).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Protein CLEC16A (CLEC16A).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein CLEC16A (CLEC16A).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein CLEC16A (CLEC16A).	[34]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein CLEC16A (CLEC16A).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein CLEC16A (CLEC16A).	[37]

References

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• [2] Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility.Nat Commun. 2017 Dec 1;8(1):1892. doi: 10.1038/s41467-017-00320-1.
• [3] Association of the C-type lectin-like domain family-16A (CLEC16A) gene polymorphisms with acute coronary syndrome in Mexican patients.Immunol Lett. 2014 Dec;162(2 Pt B):247-51. doi: 10.1016/j.imlet.2014.10.003. Epub 2014 Oct 14.
• [4] Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.Nat Commun. 2015 Jan 22;6:5966. doi: 10.1038/ncomms6966.
• [5] Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.Nat Genet. 2011 May;43(5):436-41. doi: 10.1038/ng.801. Epub 2011 Apr 3.
• [6] Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.Nat Genet. 2015 Dec;47(12):1449-1456. doi: 10.1038/ng.3424. Epub 2015 Oct 19.
• [7] The type 1 diabetes candidate gene Dexi does not affect disease risk in the nonobese diabetic mouse model.Genes Immun. 2020 Jan;21(1):71-77. doi: 10.1038/s41435-019-0083-y. Epub 2019 Aug 22.
• [8] A variant of CLEC16A gene confers protection for Vogt-Koyanagi-Harada syndrome but not for Behcet's disease in a Chinese Han population.Exp Eye Res. 2015 Mar;132:225-30. doi: 10.1016/j.exer.2015.01.004. Epub 2015 Jan 7.
• [9] Autoimmune disease association signals in CIITA and KIAA0350 are not involved in celiac disease susceptibility.Tissue Antigens. 2009 Apr;73(4):326-9. doi: 10.1111/j.1399-0039.2009.01216.x.
• [10] Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells.Nat Commun. 2015 Apr 20;6:6804. doi: 10.1038/ncomms7804.
• [11] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [12] Genetic variants at the 16p13 locus confer risk for eosinophilic esophagitis.Genes Immun. 2019 Apr;20(4):281-292. doi: 10.1038/s41435-018-0034-z. Epub 2018 Jun 8.
• [13] A CLEC16A variant confers risk for juvenile idiopathic arthritis and anti-cyclic citrullinated peptide antibody negative rheumatoid arthritis.Ann Rheum Dis. 2010 Aug;69(8):1471-4. doi: 10.1136/ard.2009.114934. Epub 2009 Sep 3.
• [14] Post-mortem multiple sclerosis lesion pathology is influenced by single nucleotide polymorphisms.Brain Pathol. 2020 Jan;30(1):106-119. doi: 10.1111/bpa.12760. Epub 2019 Jul 23.
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• [16] International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.Nat Commun. 2015 Sep 22;6:8019. doi: 10.1038/ncomms9019.
• [17] Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):269-273. doi: 10.1038/ng.3745. Epub 2016 Dec 19.
• [18] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [19] A genome-wide meta-analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order.J Allergy Clin Immunol. 2011 Nov;128(5):996-1005. doi: 10.1016/j.jaci.2011.08.030.
• [20] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
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• [22] Contribution of Rare and Common Genetic Variants to Plasma Lipid Levels and Carotid Stiffness and Geometry: A Substudy of the Paris Prospective Study 3.Circ Cardiovasc Genet. 2015 Aug;8(4):628-36. doi: 10.1161/CIRCGENETICS.114.000979. Epub 2015 Jul 9.
• [23] More CLEC16A gene variants associated with multiple sclerosis.Acta Neurol Scand. 2011 Jun;123(6):400-6. doi: 10.1111/j.1600-0404.2010.01421.x. Epub 2010 Sep 16.
• [24] Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.J Allergy Clin Immunol. 2014 Jun;133(6):1564-71. doi: 10.1016/j.jaci.2013.10.030. Epub 2013 Dec 31.
• [25] Clec16a is Critical for Autolysosome Function and Purkinje Cell Survival. Sci Rep. 2016 Mar 18;6:23326. doi: 10.1038/srep23326.
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• [28] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [29] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [30] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [31] 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.
• [32] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [35] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [36] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [37] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [38] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.