Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDH3MR4)

• DOT Name: Kinesin-like protein KIF6 (KIF6)
• Gene Name: KIF6
• Related Disease:
  Intellectual disability
  Acute coronary syndrome
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Coronary atherosclerosis
  Myocardial infarction
  Non-insulin dependent diabetes
  Cardiovascular disease
  Stroke
• UniProt ID: KIF6_HUMAN
• Pfam ID: PF00225
• Sequence:
  MVKQTIQIFARVKPPVRKHQQGIYSIDEDEKLIPSLEIILPRDLADGFVNNKRESYKFKF
  QRIFDQDANQETVFENIAKPVAGSVLAGYNGTIFAYGQTGSGKTFTITGGAERYSDRGII
  PRTLSYIFEQLQKDSSKIYTTHISYLEIYNECGYDLLDPRHEASSLEDLPKVTILEDPDQ
  NIHLKNLTLHQATTEEEALNLLFLGDTNRMIAETPMNQASTRSHCIFTIHLSSKEPGSAT
  VRHAKLHLVDLAGSERVAKTGVGGHLLTEAKYINLSLHYLEQVIIALSEKHRSHIPYRNS
  MMTSVLRDSLGGNCMTTMIATLSLEKRNLDESISTCRFAQRVALIKNEAVLNEEINPRLV
  IKRLQKEIQELKDELAMVTGEQRTEALTEAELLQLEKLITSFLEDQDSDSRLEVGADMRK
  VHHCFHHLKKLLNDKKILENNTVSSESKDQDCQEPLKEEEYRKLRDILKQRDNEINILVN
  MLKKEKKKAQEALHLAGMDRREFRQSQSPPFRLGNPEEGQRMRLSSAPSQAQDFSILGKR
  SSLLHKKIGMREEMSLGCQEAFEIFKRDHADSVTIDDNKQILKQRFSEAKALGESINEAR
  SKIGHLKEEITQRHIQQVALGISENMAVPLMPDQQEEKLRSQLEEEKRRYKTMFTRLKAL
  KVEIEHLQLLMDKAKVKLQKEFEVWWAEEATNLQVNSPAVNSLDHTKPFLQTSDSQHEWS
  QLLSNKSSGGWEVQDQGTGRFDVCDVNARKILPSPCPSPHSQKQSSTSTPLEDSIPKRPV
  SSIPLTGDSQTDSDIIAFIKARQSILQKQCLGSN
• KEGG Pathway: Motor proteins (hsa04814)
• Reactome Pathway:
  Kinesins (R-HSA-983189)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[4]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[5]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Cardiovascular disease	DIS2IQDX	Limited	Genetic Variation	[8]
Stroke	DISX6UHX	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Simvastatin	DM30SGU	Approved	Kinesin-like protein KIF6 (KIF6) increases the Cardiovascular disorder ADR of Simvastatin.	[18]
Pravastatin	DM6A0X7	Approved	Kinesin-like protein KIF6 (KIF6) increases the Cardiovascular disorder ADR of Pravastatin.	[18]
Rosuvastatin	DMMIQ7G	Approved	Kinesin-like protein KIF6 (KIF6) increases the Cardiovascular disorder ADR of Rosuvastatin.	[18]
Atorvastatin	DMF28YC	Phase 3 Trial	Kinesin-like protein KIF6 (KIF6) increases the response to substance of Atorvastatin.	[19]

7 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 Kinesin-like protein KIF6 (KIF6).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kinesin-like protein KIF6 (KIF6).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Kinesin-like protein KIF6 (KIF6).	[13]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Kinesin-like protein KIF6 (KIF6).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Kinesin-like protein KIF6 (KIF6).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kinesin-like protein KIF6 (KIF6).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Kinesin-like protein KIF6 (KIF6).	[17]

3 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 Kinesin-like protein KIF6 (KIF6).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Kinesin-like protein KIF6 (KIF6).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kinesin-like protein KIF6 (KIF6).	[16]

References

• [1] Mutations in Kinesin family member 6 reveal specific role in ependymal cell ciliogenesis and human neurological development.PLoS Genet. 2018 Nov 26;14(11):e1007817. doi: 10.1371/journal.pgen.1007817. eCollection 2018 Nov.
• [2] Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study.J Am Coll Cardiol. 2008 Jan 29;51(4):449-55. doi: 10.1016/j.jacc.2007.10.017.
• [3] KIF6 719Arg allele is associated with statin effects on cholesterol levels in amnestic mild cognitive impairment and Alzheimer's disease patients.J Alzheimers Dis. 2013;33(1):111-6. doi: 10.3233/JAD-2012-121015.
• [4] Genetic variants of connexin37 are associated with carotid intima-medial thickness and future onset of ischemic stroke.Atherosclerosis. 2011 Jan;214(1):101-6. doi: 10.1016/j.atherosclerosis.2010.10.010. Epub 2010 Oct 16.
• [5] Association between KIF6 rs20455 polymorphism and the risk of coronary heart disease (CHD): a pooled analysis of 50 individual studies including 40,059 cases and 64,032 controls.Lipids Health Dis. 2018 Jan 5;17(1):4. doi: 10.1186/s12944-017-0651-y.
• [6] The Trp719Arg polymorphism of the KIF6 gene and coronary heart disease risk: systematic review and meta-analysis.Hereditas. 2015 Oct 22;152:3. doi: 10.1186/s41065-015-0004-7. eCollection 2015.
• [7] Novel KIF6 polymorphism increases susceptibility to type 2 diabetes mellitus and coronary heart disease in Han Chinese men.J Diabetes Res. 2014;2014:871439. doi: 10.1155/2014/871439. Epub 2014 Dec 31.
• [8] KIF6 gene as a pharmacogenetic marker for lipid-lowering effect in statin treatment.PLoS One. 2018 Oct 10;13(10):e0205430. doi: 10.1371/journal.pone.0205430. eCollection 2018.
• [9] KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly.Atherosclerosis. 2012 Feb;220(2):456-62. doi: 10.1016/j.atherosclerosis.2011.11.037. Epub 2011 Dec 7.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [12] 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.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] 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.
• [17] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [18] Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J Am Coll Cardiol. 2008 Jan 29;51(4):435-43. doi: 10.1016/j.jacc.2007.05.057.
• [19] [Association of a polymorphic marker Trp719Arg of KIF6 gene with effects of atorvastatin and simvastatin in patients with early ischemic heart disease]. Kardiologiia. 2011;51(9):4-12.