Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2XLTB2)

• DOT Name: Platelet endothelial aggregation receptor 1 (PEAR1)
• Synonyms: hPEAR1; Multiple epidermal growth factor-like domains protein 12; Multiple EGF-like domains protein 12
• Gene Name: PEAR1
• Related Disease:
  Acute coronary syndrome
  Acute myocardial infarction
  Coronary atherosclerosis
  Coronary heart disease
  Coxopodopatellar syndrome
  High blood pressure
  Myocardial infarction
  Cardiovascular disease
  Venous thromboembolism
• UniProt ID: PEAR1_HUMAN
• Pfam ID: PF00053
• Sequence:
  MSPPLCPLLLLAVGLRLAGTLNPSDPNTCSFWESFTTTTKESHSRPFSLLPSEPCERPWE
  GPHTCPQPTVVYRTVYRQVVKTDHRQRLQCCHGFYESRGFCVPLCAQECVHGRCVAPNQC
  QCVPGWRGDDCSSECAPGMWGPQCDKPCSCGNNSSCDPKSGVCSCPSGLQPPNCLQPCTP
  GYYGPACQFRCQCHGAPCDPQTGACFCPAERTGPSCDVSCSQGTSGFFCPSTHSCQNGGV
  FQTPQGSCSCPPGWMGTICSLPCPEGFHGPNCSQECRCHNGGLCDRFTGQCRCAPGYTGD
  RCREECPVGRFGQDCAETCDCAPDARCFPANGACLCEHGFTGDRCTDRLCPDGFYGLSCQ
  APCTCDREHSLSCHPMNGECSCLPGWAGLHCNESCPQDTHGPGCQEHCLCLHGGVCQATS
  GLCQCAPGYTGPHCASLCPPDTYGVNCSARCSCENAIACSPIDGECVCKEGWQRGNCSVP
  CPPGTWGFSCNASCQCAHEAVCSPQTGACTCTPGWHGAHCQLPCPKGQFGEGCASRCDCD
  HSDGCDPVHGRCQCQAGWMGARCHLSCPEGLWGVNCSNTCTCKNGGTCLPENGNCVCAPG
  FRGPSCQRSCQPGRYGKRCVPCKCANHSFCHPSNGTCYCLAGWTGPDCSQPCPPGHWGEN
  CAQTCQCHHGGTCHPQDGSCICPLGWTGHHCLEGCPLGTFGANCSQPCQCGPGEKCHPET
  GACVCPPGHSGAPCRIGIQEPFTVMPTTPVAYNSLGAVIGIAVLGSLVVALVALFIGYRH
  WQKGKEHHHLAVAYSSGRLDGSEYVMPDVPPSYSHYYSNPSYHTLSQCSPNPPPPNKVPG
  PLFASLQNPERPGGAQGHDNHTTLPADWKHRREPPPGPLDRGSSRLDRSYSYSYSNGPGP
  FYNKGLISEEELGASVASLSSENPYATIRDLPSLPGGPRESSYMEMKGPPSGSPPRQPPQ
  FWDSQRRRQPQPQRDSGTYEQPSPLIHDRDSVGSQPPLPPGLPPGHYDSPKNSHIPGHYD
  LPPVRHPPSPPLRRQDR
• Function: Required for SVEP1-mediated platelet activation, via its interaction with SVEP1 and subsequent activation of AKT/mTOR signaling. May be involved in the early stages of hematopoiesis.
• Tissue Specificity: Expressed in umbilical vein endothelial cells and platelets (at protein level) . Expressed in coronary artery smooth muscle cells (at protein level) . Expressed in heart, kidney, skeletal muscle, pancreas, ovary, breast, lung, brain cortex, hypothalamus, spinal cord, dorsal root ganglion . Expressed in umbilical artery endothelial cells, megakaryocytes, osteoblasts, coronary muscle and erythroid cells .

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[1]
Acute myocardial infarction	DISE3HTG	Strong	Genetic Variation	[2]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[3]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[4]
Coxopodopatellar syndrome	DISMJAT7	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	Strong	Biomarker	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[7]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[3]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[8]

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 Platelet endothelial aggregation receptor 1 (PEAR1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Platelet endothelial aggregation receptor 1 (PEAR1).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the acetylation of Platelet endothelial aggregation receptor 1 (PEAR1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Platelet endothelial aggregation receptor 1 (PEAR1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Platelet endothelial aggregation receptor 1 (PEAR1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Platelet endothelial aggregation receptor 1 (PEAR1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Platelet endothelial aggregation receptor 1 (PEAR1).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Platelet endothelial aggregation receptor 1 (PEAR1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Platelet endothelial aggregation receptor 1 (PEAR1).	[16]

References

• [1] Genetic mutations in PEAR1 associated with cardiovascular outcomes in Chinese patients with acute coronary syndrome.Thromb Res. 2018 Mar;163:77-82. doi: 10.1016/j.thromres.2018.01.026. Epub 2018 Feb 2.
• [2] Effect of PEAR1 Genetic Variants on 1-Year Outcomes in Chinese Patients with Acute Myocardial Infarction After Percutaneous Coronary Intervention.J Atheroscler Thromb. 2018 May 1;25(5):454-459. doi: 10.5551/jat.39982. Epub 2017 Dec 5.
• [3] PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.BMC Med Genet. 2017 Apr 27;18(1):45. doi: 10.1186/s12881-017-0411-x.
• [4] Variants of PEAR1 Are Associated With Outcome in Patients With ACS and Stable CAD Undergoing PCI.Front Pharmacol. 2018 May 15;9:490. doi: 10.3389/fphar.2018.00490. eCollection 2018.
• [5] Different models of inheritance in selected genes in patients with sticky platelet syndrome and fetal loss.Semin Thromb Hemost. 2015 Apr;41(3):330-5. doi: 10.1055/s-0034-1395351. Epub 2015 Feb 19.
• [6] Hypertensive APOL1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers.PLoS One. 2019 Sep 18;14(9):e0221957. doi: 10.1371/journal.pone.0221957. eCollection 2019.
• [7] Variation of PEAR1 DNA methylation influences platelet and leukocyte function.Clin Epigenetics. 2019 Oct 29;11(1):151. doi: 10.1186/s13148-019-0744-8.
• [8] Association of Genetic Variability in Selected Genes in Patients With Deep Vein Thrombosis and Platelet Hyperaggregability.Clin Appl Thromb Hemost. 2018 Oct;24(7):1027-1032. doi: 10.1177/1076029618779136. Epub 2018 Jun 4.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [12] 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.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] 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.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.