Details of Drug Off-Target (DOT)

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

• DOT Name: Apolipoprotein A-V (APOA5)
• Synonyms: Apo-AV; ApoA-V; Apolipoprotein A5; Regeneration-associated protein 3
• Gene Name: APOA5
• Related Disease:
  Chronic kidney disease
  Familial hypercholesterolemia
  Hypercholesterolemia, familial, 1
  Primary cutaneous T-cell lymphoma
  Acute liver failure
  Acute myocardial infarction
  Alzheimer disease
  Anemia
  Arteriosclerosis
  Atherosclerosis
  Autosomal dominant familial periodic fever
  Cardiac disease
  Cardiovascular disease
  Diabetic kidney disease
  Dysbetalipoproteinemia
  Familial lipoprotein lipase deficiency
  Hepatocellular carcinoma
  High blood pressure
  Hyperinsulinemia
  Hyperlipidemia
  Hyperlipidemia, familial combined, LPL related
  Hyperlipoproteinemia
  Hyperlipoproteinemia type V
  Hypothyroidism
  Metabolic disorder
  Myocardial infarction
  Myocardial ischemia
  Obesity
  Obstructive sleep apnea
  Schizophrenia
  Stroke
  Vascular disease
  Lipid metabolism disorder
  Chronic hepatitis B virus infection
  Pancreatitis
  Prostate cancer
  Prostate carcinoma
  Sickle-cell anaemia
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: APOA5_HUMAN
• Pfam ID: PF01442
• Sequence:
  MASMAAVLTWALALLSAFSATQARKGFWDYFSQTSGDKGRVEQIHQQKMAREPATLKDSL
  EQDLNNMNKFLEKLRPLSGSEAPRLPQDPVGMRRQLQEELEEVKARLQPYMAEAHELVGW
  NLEGLRQQLKPYTMDLMEQVALRVQELQEQLRVVGEDTKAQLLGGVDEAWALLQGLQSRV
  VHHTGRFKELFHPYAESLVSGIGRHVQELHRSVAPHAPASPARLSRCVQVLSRKLTLKAK
  ALHARIQQNLDQLREELSRAFAGTGTEEGAGPDPQMLSEEVRQRLQAFRQDTYLQIAAFT
  RAIDQETEEVQQQLAPPPPGHSAFAPEFQQTDSGKVLSKLQARLDDLWEDITHSLHDQGH
  SHLGDP
• Function: Minor apolipoprotein mainly associated with HDL and to a lesser extent with VLDL. May also be associated with chylomicrons. Important determinant of plasma triglyceride (TG) levels by both being a potent stimulator of apo-CII lipoprotein lipase (LPL) TG hydrolysis and an inhibitor of the hepatic VLDL-TG production rate (without affecting the VLDL-apoB production rate). Activates poorly lecithin:cholesterol acyltransferase (LCAT) and does not enhance efflux of cholesterol from macrophages. Binds heparin.
• Tissue Specificity: Liver and plasma.
• KEGG Pathway: PPAR sig.ling pathway (hsa03320)
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Assembly of active LPL and LIPC lipase complexes (R-HSA-8963889)
  Chylomicron remodeling (R-HSA-8963901)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Biomarker	[1]
Familial hypercholesterolemia	DISC06IX	Definitive	Genetic Variation	[2]
Hypercholesterolemia, familial, 1	DISU411W	Definitive	Genetic Variation	[2]
Primary cutaneous T-cell lymphoma	DIS35WVW	Definitive	Genetic Variation	[3]
Acute liver failure	DIS5EZKX	Strong	Biomarker	[4]
Acute myocardial infarction	DISE3HTG	Strong	Genetic Variation	[5]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[6]
Anemia	DISTVL0C	Strong	Genetic Variation	[7]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[8]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[9]
Autosomal dominant familial periodic fever	DISCRNV1	Strong	Biomarker	[4]
Cardiac disease	DISVO1I5	Strong	Biomarker	[10]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[11]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[12]
Dysbetalipoproteinemia	DISNRSNM	Strong	Genetic Variation	[13]
Familial lipoprotein lipase deficiency	DIS0M7NJ	Strong	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[16]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[17]
Hyperlipidemia	DIS61J3S	Strong	Genetic Variation	[8]
Hyperlipidemia, familial combined, LPL related	DISL1CE3	Strong	Genetic Variation	[18]
Hyperlipoproteinemia	DISVBLBO	Strong	Genetic Variation	[19]
Hyperlipoproteinemia type V	DISB1KP3	Strong	Autosomal dominant	[20]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[21]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[22]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[23]
Myocardial ischemia	DISFTVXF	Strong	Genetic Variation	[24]
Obesity	DIS47Y1K	Strong	Biomarker	[25]
Obstructive sleep apnea	DIS0SVD1	Strong	Biomarker	[26]
Schizophrenia	DISSRV2N	Strong	Biomarker	[27]
Stroke	DISX6UHX	Strong	Genetic Variation	[28]
Vascular disease	DISVS67S	Strong	Altered Expression	[29]
Lipid metabolism disorder	DISEOA7S	moderate	Genetic Variation	[30]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Biomarker	[31]
Pancreatitis	DIS0IJEF	Limited	Genetic Variation	[32]
Prostate cancer	DISF190Y	Limited	Biomarker	[33]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[33]
Sickle-cell anaemia	DIS5YNZB	Limited	Genetic Variation	[34]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[35]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Apolipoprotein A-V (APOA5).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Apolipoprotein A-V (APOA5).	[43]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Apolipoprotein A-V (APOA5).	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Apolipoprotein A-V (APOA5).	[38]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Apolipoprotein A-V (APOA5).	[39]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Apolipoprotein A-V (APOA5).	[38]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Apolipoprotein A-V (APOA5).	[40]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Apolipoprotein A-V (APOA5).	[41]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Apolipoprotein A-V (APOA5).	[41]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Apolipoprotein A-V (APOA5).	[42]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the expression of Apolipoprotein A-V (APOA5).	[45]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Apolipoprotein A-V (APOA5).	[45]
Farnesol	DMV2X1B	Investigative	Farnesol increases the expression of Apolipoprotein A-V (APOA5).	[45]

References

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• [2] Polymorphisms in apolipoprotein E and apolipoprotein A-V do not influence the lipid response to rosuvastatin but are associated with baseline lipid levels in Chinese patients with hyperlipidemia.J Clin Lipidol. 2012 Nov-Dec;6(6):585-92. doi: 10.1016/j.jacl.2012.02.005. Epub 2012 Feb 18.
• [3] Association of APOA5 and APOC3 Genetic Polymorphisms With Severity of Hypertriglyceridemia in Patients With Cutaneous T-Cell Lymphoma Treated With Bexarotene.JAMA Dermatol. 2018 Dec 1;154(12):1424-1431. doi: 10.1001/jamadermatol.2018.3679.
• [4] Apolipoprotein A5 alleviates LPS/D-GalN-induced fulminant liver failure in mice by inhibiting TLR4-mediated NF-B pathway.J Transl Med. 2019 May 10;17(1):151. doi: 10.1186/s12967-019-1900-9.
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• [7] The Methylenetetrahydrofolate Reductase C677T (rs1801133) and Apolipoprotein A5-1131T>C (rs662799) Polymorphisms, and Anemia Are Independent Risk Factors for Ischemic Stroke.J Stroke Cerebrovasc Dis. 2018 May;27(5):1357-1362. doi: 10.1016/j.jstrokecerebrovasdis.2017.12.025. Epub 2018 Feb 3.
• [8] Magnolol-mediated regulation of plasma triglyceride through affecting lipoprotein lipase activity in apolipoprotein A5 knock-in mice.PLoS One. 2018 Feb 9;13(2):e0192740. doi: 10.1371/journal.pone.0192740. eCollection 2018.
• [9] Apolipoprotein A5 gene variants are associated with decreased adiponectin levels and increased arterial stiffness in subjects with low high-density lipoprotein-cholesterol levels.Clin Genet. 2018 Nov;94(5):438-444. doi: 10.1111/cge.13439. Epub 2018 Sep 7.
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• [12] A case-control study of apoA5 -1131T-->C polymorphism that examines the role of triglyceride levels in diabetic nephropathy.J Diabetes Complications. 2007 May-Jun;21(3):158-63. doi: 10.1016/j.jdiacomp.2006.02.003.
• [13] Cerebrovascular atherosclerosis in type III hyperlipidemia is modulated by variation in the apolipoprotein A5 gene.Eur J Med Res. 2011 Feb 24;16(2):79-84. doi: 10.1186/2047-783x-16-2-79.
• [14] Clinical whole exome sequencing in severe hypertriglyceridemia.Clin Chim Acta. 2019 Jan;488:31-39. doi: 10.1016/j.cca.2018.10.041. Epub 2018 Oct 30.
• [15] The role of apolipoprotein A5 in non-alcoholic fatty liver disease.Gut. 2011 Jul;60(7):985-91. doi: 10.1136/gut.2010.222224. Epub 2011 Feb 21.
• [16] APOA5 rs651821 confers increased risk for hypertension in Tongdao Dong population.Clin Exp Hypertens. 2020;42(1):81-85. doi: 10.1080/10641963.2019.1590383. Epub 2019 Mar 30.
• [17] Insulin-mediated down-regulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway: role of upstream stimulatory factor.Mol Cell Biol. 2005 Feb;25(4):1537-48. doi: 10.1128/MCB.25.4.1537-1548.2005.
• [18] Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population.Mol Cell Probes. 2015 Feb;29(1):19-24. doi: 10.1016/j.mcp.2014.10.002. Epub 2014 Oct 13.
• [19] Mutations of the apolipoprotein A5 gene with inherited hypertriglyceridaemia: review of the current literature.Curr Med Chem. 2012;19(36):6163-70. doi: 10.2174/092986712804485719.
• [20] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
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• [22] The paradox of ApoA5 modulation of triglycerides: evidence from clinical and basic research.Clin Biochem. 2013 Jan;46(1-2):12-9. doi: 10.1016/j.clinbiochem.2012.09.007. Epub 2012 Sep 19.
• [23] Frameshift mutation in the APOA5 gene causing hypertriglyceridemia in a Pakistani family: Management and considerations for cardiovascular risk.J Clin Lipidol. 2016 Sep-Oct;10(5):1272-7. doi: 10.1016/j.jacl.2016.07.009. Epub 2016 Aug 9.
• [24] Apolipoprotein A5 gene promoter region T-1131C polymorphism associates with elevated circulating triglyceride levels and confers susceptibility for development of ischemic stroke.J Mol Neurosci. 2006;29(2):177-83. doi: 10.1385/JMN:29:2:177.
• [25] New Insights into Apolipoprotein A5 and the Modulation of Human Adipose-derived Mesenchymal Stem Cells Adipogenesis.Curr Mol Med. 2020;20(2):144-156. doi: 10.2174/1566524019666190927155702.
• [26] Serum high-density lipoprotein correlates with serum apolipoprotein M and A5 in obstructive sleep apnea hypopnea syndrome.Sleep Breath. 2017 Mar;21(1):37-44. doi: 10.1007/s11325-016-1357-5. Epub 2016 May 21.
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• [28] Genetic and lifestyle predictors of ischemic stroke severity and outcome.Neurol Sci. 2019 Dec;40(12):2565-2572. doi: 10.1007/s10072-019-04006-y. Epub 2019 Jul 20.
• [29] Rs964184 (APOA5-A4-C3-A1) is related to elevated plasma triglyceride levels, but not to an increased risk for vascular events in patients with clinically manifest vascular disease.PLoS One. 2014 Jun 30;9(6):e101082. doi: 10.1371/journal.pone.0101082. eCollection 2014.
• [30] Association of apolipoprotein A5 genetic polymorphisms with steroid-induced osteonecrosis of femoral head in a Chinese Han population.Diagn Pathol. 2014 Dec 17;9:229. doi: 10.1186/s13000-014-0229-1.
• [31] Plasma Apolipoprotein A-V Predicts Long-term Survival in Chronic Hepatitis B Patients with Acute-on-Chronic Liver Failure.Sci Rep. 2017 Mar 30;7:45576. doi: 10.1038/srep45576.
• [32] Severe hypertriglyceridaemia and pancreatitis in a patient with lipoprotein lipase deficiency based on mutations in lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) genes.BMJ Case Rep. 2019 Apr 3;12(4):e228199. doi: 10.1136/bcr-2018-228199.
• [33] Genetic variants reflecting higher vitamin e status in men are associated with reduced risk of prostate cancer.J Nutr. 2014 May;144(5):729-33. doi: 10.3945/jn.113.189928. Epub 2014 Mar 12.
• [34] Polymorphisms in genes that affect the variation of lipid levels in a Brazilian pediatric population with sickle cell disease: rs662799 APOA5 and rs964184 ZPR1.Blood Cells Mol Dis. 2020 Feb;80:102376. doi: 10.1016/j.bcmd.2019.102376. Epub 2019 Oct 22.
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