Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDD93KB)

• DOT Name: Hereditary hemochromatosis protein (HFE)
• Synonyms: HLA-H
• Gene Name: HFE
• Related Disease:
  Hemochromatosis
  Iron-deficiency anemia
  Adrenoleukodystrophy
  Anxiety
  Arthritis
  Astrocytoma
  Autism spectrum disorder
  Beta thalassemia
  Carcinoma of liver and intrahepatic biliary tract
  Cardiomyopathy
  Childhood acute lymphoblastic leukemia
  Coeliac disease
  Colorectal carcinoma
  Congestive heart failure
  Familial hypocalciuric hypercalcemia 1
  Glioma
  Gout
  Hematologic disease
  Hemochromatosis type 3
  Hemolytic anemia
  Hepatitis
  Hereditary spherocytosis
  Iron metabolism disease
  leukaemia
  Leukemia
  Liver cancer
  Neuroblastoma
  Non-alcoholic steatohepatitis
  Osteoarthritis
  Osteoporosis
  Parkinsonian disorder
  Porphyria
  Rheumatoid arthritis
  Stroke
  Variegate porphyria
  Wilson disease
  Alpha-1 antitrypsin deficiency
  Cystic fibrosis
  Dementia
  Dilated cardiomyopathy 1A
  Hepatitis B virus infection
  Multiple sclerosis
  Acute lymphocytic leukaemia
  Alcohol use disorder
  Chondrocalcinosis
  Familial Alzheimer disease
  Hemochromatosis type 4
  High blood pressure
• UniProt ID: HFE_HUMAN
• PDB ID: 1A6Z; 1DE4
• Pfam ID: PF07654 ; PF00129
• Sequence:
  MGPRARPALLLLMLLQTAVLQGRLLRSHSLHYLFMGASEQDLGLSLFEALGYVDDQLFVF
  YDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTVDFWTIMENHNHSKESHTLQV
  ILGCEMQEDNSTEGYWKYGYDGQDHLEFCPDTLDWRAAEPRAWPTKLEWERHKIRARQNR
  AYLERDCPAQLQQLLELGRGVLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWL
  KDKQPMDAKEFEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWEPS
  PSGTLVIGVISGIAVFVVILFIGILFIILRKRQGSRGAMGHYVLAERE
• Function: Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.
• Tissue Specificity: Expressed in all tissues tested except brain.
• KEGG Pathway: TGF-beta sig.ling pathway (hsa04350)
• Reactome Pathway: Transferrin endocytosis and recycling (R-HSA-917977)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hemochromatosis	DISAPY0H	Definitive	Autosomal recessive	[1]
Iron-deficiency anemia	DIS0VQYF	Definitive	Biomarker	[2]
Adrenoleukodystrophy	DISTUD1F	Strong	Genetic Variation	[3]
Anxiety	DISIJDBA	Strong	Genetic Variation	[4]
Arthritis	DIST1YEL	Strong	Genetic Variation	[5]
Astrocytoma	DISL3V18	Strong	Biomarker	[6]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[7]
Beta thalassemia	DIS5RCQK	Strong	Genetic Variation	[8]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[9]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[10]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[11]
Coeliac disease	DISIY60C	Strong	Biomarker	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[13]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[14]
Familial hypocalciuric hypercalcemia 1	DISPW6O5	Strong	Biomarker	[15]
Glioma	DIS5RPEH	Strong	Genetic Variation	[16]
Gout	DISHC0U7	Strong	Genetic Variation	[17]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[18]
Hemochromatosis type 3	DIS64BFY	Strong	Biomarker	[19]
Hemolytic anemia	DIS803XQ	Strong	Genetic Variation	[20]
Hepatitis	DISXXX35	Strong	Genetic Variation	[21]
Hereditary spherocytosis	DISQYJP5	Strong	Genetic Variation	[22]
Iron metabolism disease	DISWDM9J	Strong	Biomarker	[23]
leukaemia	DISS7D1V	Strong	Genetic Variation	[24]
Leukemia	DISNAKFL	Strong	Genetic Variation	[24]
Liver cancer	DISDE4BI	Strong	Biomarker	[9]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[25]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[26]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[27]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[28]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[29]
Porphyria	DIS9YL4C	Strong	Genetic Variation	[30]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[31]
Stroke	DISX6UHX	Strong	Genetic Variation	[32]
Variegate porphyria	DIS8OK5W	Strong	Genetic Variation	[33]
Wilson disease	DISVS9H7	Strong	Genetic Variation	[34]
Alpha-1 antitrypsin deficiency	DISQKEHW	moderate	Genetic Variation	[35]
Cystic fibrosis	DIS2OK1Q	moderate	Genetic Variation	[36]
Dementia	DISXL1WY	moderate	Genetic Variation	[32]
Dilated cardiomyopathy 1A	DIS0RK9Z	moderate	Biomarker	[37]
Hepatitis B virus infection	DISLQ2XY	moderate	Biomarker	[38]
Multiple sclerosis	DISB2WZI	moderate	Genetic Variation	[39]
Acute lymphocytic leukaemia	DISPX75S	Limited	Genetic Variation	[24]
Alcohol use disorder	DISMB65Y	Limited	Genetic Variation	[40]
Chondrocalcinosis	DISP4AHX	Limited	Genetic Variation	[41]
Familial Alzheimer disease	DISE75U4	Limited	Biomarker	[42]
Hemochromatosis type 4	DIS7240J	Limited	Biomarker	[19]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[43]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Hereditary hemochromatosis protein (HFE) decreases the response to substance of Arsenic trioxide.	[53]
Paraquat	DMR8O3X	Investigative	Hereditary hemochromatosis protein (HFE) decreases the response to substance of Paraquat.	[54]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Hereditary hemochromatosis protein (HFE).	[44]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hereditary hemochromatosis protein (HFE).	[45]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hereditary hemochromatosis protein (HFE).	[46]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Hereditary hemochromatosis protein (HFE).	[47]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Hereditary hemochromatosis protein (HFE).	[48]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Hereditary hemochromatosis protein (HFE).	[49]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Hereditary hemochromatosis protein (HFE).	[50]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hereditary hemochromatosis protein (HFE).	[51]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Hereditary hemochromatosis protein (HFE).	[52]

References

• [1] 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.
• [2] The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease.Am J Hematol. 2018 Mar;93(3):383-393. doi: 10.1002/ajh.24991. Epub 2017 Dec 18.
• [3] HFE gene mutations in patients with alcoholic liver disease. A prospective study from northwestern Poland.Pol Arch Med Wewn. 2010 Apr;120(4):127-31.
• [4] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [5] Hereditary hemochromatosis should be considered a conformational disorder.Med Hypotheses. 2008;70(4):783-4. doi: 10.1016/j.mehy.2007.07.041. Epub 2007 Sep 29.
• [6] HFE polymorphisms affect cellular glutamate regulation.Neurobiol Aging. 2011 Jun;32(6):1114-23. doi: 10.1016/j.neurobiolaging.2009.05.016. Epub 2009 Jun 26.
• [7] Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders.Genet Med. 2010 Nov;12(11):694-702. doi: 10.1097/GIM.0b013e3181f0c5f3.
• [8] HFE gene mutations in Brazilian thalassemic patients.Braz J Med Biol Res. 2006 Dec;39(12):1575-80. doi: 10.1590/s0100-879x2006005000041.
• [9] Regression of Fibrosis Stage With Treatment Reduces Long-Term Risk of Liver Cancer in Patients With Hemochromatosis Caused by Mutation in HFE.Clin Gastroenterol Hepatol. 2020 Jul;18(8):1851-1857. doi: 10.1016/j.cgh.2019.10.010. Epub 2019 Oct 14.
• [10] A Mouse Model of Cardiomyopathy Induced by Mutations in the Hemochromatosis HFE Gene.Can J Cardiol. 2017 Jul;33(7):904-910. doi: 10.1016/j.cjca.2017.03.006. Epub 2017 Mar 15.
• [11] HFE gene mutation and iron overload in Egyptian pediatric acute lymphoblastic leukemia survivors: a single-center study.Hematology. 2017 Aug;22(7):398-404. doi: 10.1080/10245332.2017.1289324. Epub 2017 Feb 17.
• [12] Mainstreaming of genomic medicine in gastroenterology, present and future: a nationwide survey of UK gastroenterology trainees.BMJ Open. 2019 Oct 22;9(10):e030505. doi: 10.1136/bmjopen-2019-030505.
• [13] Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.Am J Hum Genet. 2019 Sep 5;105(3):526-533. doi: 10.1016/j.ajhg.2019.07.012. Epub 2019 Aug 15.
• [14] Successful Treatment of Iron-Overload Cardiomyopathy in Hereditary Hemochromatosis With Deferoxamine and Deferiprone.Can J Cardiol. 2016 Dec;32(12):1574.e1-1574.e3. doi: 10.1016/j.cjca.2016.07.589. Epub 2016 Jul 28.
• [15] R2*-relaxometry of the pancreas in patients with human hemochromatosis protein associated hereditary hemochromatosis.Eur J Radiol. 2017 Apr;89:149-155. doi: 10.1016/j.ejrad.2017.02.006. Epub 2017 Feb 5.
• [16] HFE polymorphisms affect survival of brain tumor patients.J Neurooncol. 2015 Mar;122(1):97-104. doi: 10.1007/s11060-014-1681-1. Epub 2014 Dec 10.
• [17] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [18] Analogues of desferrioxamine B designed to attenuate iron-mediated neurodegeneration: synthesis, characterisation and activity in the MPTP-mouse model of Parkinson's disease.Metallomics. 2017 Jul 19;9(7):852-864. doi: 10.1039/c7mt00039a.
• [19] Current approach to hemochromatosis.Blood Rev. 2008 Jul;22(4):195-210. doi: 10.1016/j.blre.2008.03.001. Epub 2008 Apr 21.
• [20] Inherited or acquired modifiers of iron status may dramatically affect the phenotype in dehydrated hereditary stomatocytosis.Eur J Haematol. 2018 Oct;101(4):566-569. doi: 10.1111/ejh.13135. Epub 2018 Aug 31.
• [21] Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma.Blood Cells Mol Dis. 2005 Jul-Aug;35(1):27-32. doi: 10.1016/j.bcmd.2005.03.007.
• [22] Fatal Cardiac Hemochromatosis in a Patient with Hereditary Spherocytosis.Int Heart J. 2018 Mar 30;59(2):427-430. doi: 10.1536/ihj.17-160. Epub 2018 Mar 20.
• [23] H63D mutation in hemochromatosis alters cholesterol metabolism and induces memory impairment.Neurobiol Aging. 2014 Jun;35(6):1511.e1-12. doi: 10.1016/j.neurobiolaging.2013.12.014. Epub 2013 Dec 25.
• [24] Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia.Cancer. 2013 Oct 1;119(19):3555-62. doi: 10.1002/cncr.28256. Epub 2013 Jul 16.
• [25] HFE genotype affects exosome phenotype in cancer.Biochim Biophys Acta Gen Subj. 2017 Aug;1861(8):1921-1928. doi: 10.1016/j.bbagen.2017.05.014. Epub 2017 May 17.
• [26] Serum ferritin is a clinical biomarker in Japanese patients with nonalcoholic steatohepatitis (NASH) independent of HFE gene mutation.Dig Dis Sci. 2010 Mar;55(3):808-14. doi: 10.1007/s10620-009-0771-y. Epub 2009 Mar 7.
• [27] HFE hemochromatosis screening in patients with severe hip osteoarthritis: A prospective cross-sectional study.PLoS One. 2018 Nov 14;13(11):e0207415. doi: 10.1371/journal.pone.0207415. eCollection 2018.
• [28] Association between iron overload and osteoporosis in patients with hereditary hemochromatosis.Osteoporos Int. 2009 Apr;20(4):549-55. doi: 10.1007/s00198-008-0701-4. Epub 2008 Jul 26.
• [29] Mutations in the hemochromatosis gene (HFE), Parkinson's disease and parkinsonism.Neurosci Lett. 2003 Sep 11;348(2):117-9. doi: 10.1016/s0304-3940(03)00713-4.
• [30] Porphyria cutanea tarda: Recent update.Mol Genet Metab. 2019 Nov;128(3):271-281. doi: 10.1016/j.ymgme.2019.01.004. Epub 2019 Jan 18.
• [31] Manifestation of rheumatoid arthritis in a patient with hereditary haemochromatosis.Rheumatol Int. 2006 Aug;26(10):939-41. doi: 10.1007/s00296-006-0113-8. Epub 2006 Feb 9.
• [32] Risk factors for development of dementia in a unique six-year cohort study. I. An exploratory, pilot study of involvement of the E4 allele of apolipoprotein E, mutations of the hemochromatosis-HFE gene, type 2 diabetes, and stroke.J Alzheimers Dis. 2014;38(4):907-22. doi: 10.3233/JAD-131409.
• [33] Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria.Hum Mol Genet. 1999 Aug;8(8):1517-22. doi: 10.1093/hmg/8.8.1517.
• [34] Iron metabolism and the role of HFE gene polymorphisms in Wilson disease.Liver Int. 2012 Jan;32(1):165-70. doi: 10.1111/j.1478-3231.2011.02661.x. Epub 2011 Oct 17.
• [35] ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency.PLoS One. 2017 Jun 15;12(6):e0179369. doi: 10.1371/journal.pone.0179369. eCollection 2017.
• [36] Mutations in the HFE gene can be associated with increased lung disease severity in cystic fibrosis.Gene. 2019 Jan 30;683:12-17. doi: 10.1016/j.gene.2018.10.002. Epub 2018 Oct 3.
• [37] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [38] Hepatitis B virus DNA integration in tumour tissue of a non-cirrhotic HFE-haemochromatosis patient with hepatocellular carcinoma.J Hepatol. 2013 Jan;58(1):190-3. doi: 10.1016/j.jhep.2012.09.005. Epub 2012 Sep 16.
• [39] Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis.BMC Med Genet. 2012 Aug 10;13:70. doi: 10.1186/1471-2350-13-70.
• [40] Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin.Gastroenterology. 2015 Oct;149(5):1240-1251.e4. doi: 10.1053/j.gastro.2015.06.045. Epub 2015 Jul 9.
• [41] The H63D variant in the HFE gene predisposes to arthralgia, chondrocalcinosis and osteoarthritis.Ann Rheum Dis. 2007 Nov;66(11):1436-42. doi: 10.1136/ard.2006.063099. Epub 2007 Feb 6.
• [42] Iron genes, iron load and risk of Alzheimer's disease.J Med Genet. 2006 Oct;43(10):e52. doi: 10.1136/jmg.2006.040519.
• [43] HFE H63D Polymorphism and the Risk for Systemic Hypertension, Myocardial Remodeling, and Adverse Cardiovascular Events in the ARIC Study.Hypertension. 2019 Jan;73(1):68-74. doi: 10.1161/HYPERTENSIONAHA.118.11730.
• [44] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [45] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [46] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [47] 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.
• [48] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [49] 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.
• [50] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [51] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [52] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.
• [53] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [54] HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers. Toxicol Sci. 2021 Apr 27;181(1):47-57. doi: 10.1093/toxsci/kfab020.