EPO

Summary

EPO (erythropoietin, HGNC:3415) is a protein-coding gene on chromosome 7q22.1, encoding Erythropoietin (P01588). Hormone involved in the regulation of erythrocyte proliferation and differentiation and the maintenance of a physiological level of circulating erythrocyte mass.

This gene encodes a secreted, glycosylated cytokine composed of four alpha helical bundles. The encoded protein is mainly synthesized in the kidney, secreted into the blood plasma, and binds to the erythropoietin receptor to promote red blood cell production, or erythropoiesis, in the bone marrow. Expression of this gene is upregulated under hypoxic conditions, in turn leading to increased erythropoiesis and enhanced oxygen-carrying capacity of the blood. Expression of this gene has also been observed in brain and in the eye, and elevated expression levels have been observed in diabetic retinopathy and ocular hypertension. Recombinant forms of the encoded protein exhibit neuroprotective activity against a variety of potential brain injuries, as well as antiapoptotic functions in several tissue types, and have been used in the treatment of anemia and to enhance the efficacy of cancer therapies.

Source: NCBI Gene 2056 — RefSeq curated summary.

At a glance

• Gene–disease (curated): erythrocytosis, familial, 5 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 23
• Clinical variants (ClinVar): 63 total — 6 pathogenic
• Phenotypes (HPO): 9
• Druggable target: yes
• MANE Select transcript: NM_000799

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3415
Approved symbol	EPO
Name	erythropoietin
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	EP
Ensembl gene	ENSG00000130427
Ensembl biotype	protein_coding
OMIM	133170
Entrez	2056

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000252723

RefSeq mRNA: 1 — MANE Select: NM_000799 NM_000799

CCDS: CCDS5705

Canonical transcript exons

ENST00000252723 — 5 exons

Exon	Start	End
ENSE00000894545	100722978	100723700
ENSE00001130416	100722664	100722843
ENSE00001130423	100721962	100722048
ENSE00001130431	100720468	100720993
ENSE00001144077	100721558	100721703

Expression profiles

Bgee: expression breadth broad, 73 present calls, max score 77.36.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0944 / max 12.5491, expressed in 49 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80053	0.0559	25
80054	0.0385	19

Top tissues by expression

247 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	77.36	gold quality
triceps brachii	UBERON:0001509	72.07	gold quality
body of pancreas	UBERON:0001150	71.80	gold quality
gluteal muscle	UBERON:0002000	70.80	gold quality
periodontal ligament	UBERON:0008266	70.17	gold quality
liver	UBERON:0002107	68.49	gold quality
type B pancreatic cell	CL:0000169	68.24	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	67.13	gold quality
tendon of biceps brachii	UBERON:0008188	66.10	gold quality
olfactory bulb	UBERON:0002264	65.11	gold quality
biceps brachii	UBERON:0001507	64.35	gold quality
cartilage tissue	UBERON:0002418	64.15	gold quality
diaphragm	UBERON:0001103	63.66	gold quality
deltoid	UBERON:0001476	63.31	gold quality
lateral nuclear group of thalamus	UBERON:0002736	63.07	gold quality
pancreatic ductal cell	CL:0002079	62.92	silver quality
endometrium epithelium	UBERON:0004811	62.75	gold quality
trabecular bone tissue	UBERON:0002483	62.59	gold quality
endocervix	UBERON:0000458	62.34	gold quality
inferior olivary complex	UBERON:0002127	62.28	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	62.16	gold quality
quadriceps femoris	UBERON:0001377	61.93	gold quality
oral cavity	UBERON:0000167	61.91	gold quality
vastus lateralis	UBERON:0001379	61.85	gold quality
Brodmann (1909) area 23	UBERON:0013554	61.73	gold quality
endothelial cell	CL:0000115	61.48	gold quality
parotid gland	UBERON:0001831	61.09	gold quality
tongue squamous epithelium	UBERON:0006919	61.09	gold quality
decidua	UBERON:0002450	60.72	gold quality
vena cava	UBERON:0004087	60.71	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting EPO, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-4277	98.34	67.17	1323
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-4421	97.99	64.89	701
HSA-MIR-3661	97.83	67.30	705
HSA-MIR-5699-3P	97.81	65.00	861
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-7855-5P	97.39	67.18	925
HSA-MIR-122-5P	97.23	64.92	1024
HSA-MIR-6748-3P	97.20	65.66	836
HSA-MIR-631	97.05	66.93	602
HSA-MIR-711	96.60	65.75	528

Literature-anchored findings (GeneRIF, showing 40)

• used a transient global spinal ischemia model in rabbits to test whether exogenous EPO can cross the blood-spinal cord barrier and protect these motor neurons. (PMID:11854521)
• Carbohydrate content and structure of EPO are important determinants in their half-life in the circulation. (PMID:11861258)
• Erythropoietin, tumours and the von Hippel-Lindau gene: towards identification of mechanisms and dysfunction of oxygen sensing. (PMID:11865075)
• renal failure patients mounted an EPO response to hypoxia but at lower EPO levels (PMID:11869305)
• Serum erythropoietin levels (s-[epo]), haemoglobin concentration ([Hb]), haematocrit (hct), and ferritin concentration ([fer]) were measured in seven healthy male volunteers (20-23 years) exposed continuously to hypoxia (PO(2) 14 kPa) for 10 days (PMID:11906321)
• Influence of controlled hypoxia and radical scavenging agents on erythropoietin and malondialdehyde concentrations in humans. (PMID:11906322)
• Data suggest that erythropoietin may be an endogenous stimulant of blood vessel growth during neonatal gastrointestinal development. (PMID:11919332)
• Two to three weeks after initiation of hydroxyurea treatment, the sEpo values started to increase and reached levels three to 31 times higher than the baseline two to three weeks later. (PMID:11920206)
• While both Epo and Epo-R were detected in all samples of isolated epithelial cells analysed throughout the menstrual cycle, neither one was detected in isolated stromal cells. Epo and Epo-R protein expression in glandular epithelial cells was increased (PMID:11994541)
• Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB. (PMID:12091337)
• Increased levels of circulating thrombopoietin were found in patients with clonal thrombocytosis versus patients with reactive thrombocytosis, indicating a potential differential diagnosis tool. (PMID:12171772)
• data suggest that although chronic lymphocytic leukemia (CLL) anemia is not characterized by inadequate Epo production, in some CLL patients this factor may be correlated; in these cases, levels of TNF-alpha were higher than in other anemic cases (PMID:12187026)
• REVIEW: pathways by which transcription of erythropoietin is regulated by availability of molecular oxygen (PMID:12207089)
• hypoxia-inducible gene expression in human neuroblastoma cells (PMID:12239177)
• triggers a signaling pathway (MAPK p42/44) in vascular endothelial cells and increases the thrombogenicity of their extracellular matrices (PMID:12362243)
• All regions of kidney express erythropoietin receptors. Review. (PMID:12381912)
• erythropoietin signalling contributes to the growth and/or survival of both transformed cells and capillary endothelial cells in female reproductive system tumours. (PMID:12419827)
• Direct comparison of nonglycosylated vs. glycosylated EPO demonstrates how both carbohydrate core structure and sialic acid can dampen electrostatic contributions to receptor association rate constant with little effect on dissociation rate. (PMID:12463751)
• may play an important role in signal transduction via EpoR on erythroid progenitor in CRF patients. (PMID:12476588)
• a key role for NF-kappaB in EPO gene regulation in response to hypoxia (PMID:12482504)
• Epo and Epo-R localized within glandular epithelial cells in both peritoneal endometriosis and eutopic endometrium. Role in pathophysiology of endometriosis. (PMID:12525458)
• Inhibition of erythropoietin(Epo) gene expression by cadmium depends on suppression of hypoxia-inducible factor 1(HIF-1) binding activity. (PMID:12734640)
• Results suggest that increased expression of erythropoietin may play a significant role in cervical carcinogenesis and tumor progression. (PMID:12759237)
• hemoglobin levels are related to the rise in serum EPO that occurs during pregnancy (PMID:12801298)
• protein CBP/p300 was shown to be essential for EPO- and SCF-mediated STAT5 transactivation (PMID:12829027)
• Novel function for EPO by providing in vivo evidence for a physiological role during fibrin-induced wound healing. (PMID:12937140)
• These findings suggest that recombinant human erythropoietin (EPO) attenuates ischemia-induced inflammation by reducing neuronal death rather than by direct effects upon EPO-receptor-expressing inflammatory cells. (PMID:12975460)
• GATA-4 is critical for transcription of the Epo gene in hepatocytes and may contribute to the switch in the site of Epo gene expression from the fetal liver to the adult kidney (PMID:14583613)
• Only a minority of papillary thyroid carcinomas (PTC) expressed EPO, and there were no significant differences between the PTC that did or did not express EPO. (PMID:14584755)
• after rHuEpo stimulation in the chick embryo chorioallantoic membrane assay, the generation of new blood vessels occurred more frequently following an intussusceptive microvascular growth mechanism (PMID:14671634)
• EPO stimulation significantly increased the level of Akt phosphorylation, the downstream target of PI3-kinase. (PMID:14704034)
• Overexpression of EPO protects islets from destruction and does not compromise islet function. Genetic engineering with EPO may improve islet survival and engraftment in transplant setting, but regulation of gene expression will be important prerequisite. (PMID:14724429)
• Results show that recombinant human erythropoietin reduces brain injury, especially apoptotic cell death, after neonatal hypoxia-ischemia. (PMID:14747752)
• Erythropoietin deficiency may be one of the endocrine abnormalities associated with autoimmune polyglandular syndrome type I. (PMID:14755373)
• EPO levels increased incompensatively in anemia of chronic disease (ACD) children, which may be a cause of ACD. (PMID:14990112)
• Erythropoietin protein was constitutively present in seminal plasma. The seminal EPO originated from the prostate and seminal vesicle. No association between EPO levels in seminal plasma and sperm parameters was found. (PMID:15019812)
• Review summarizes current knowledge of the nonerythropoietic roles of Epo, its neurotrophic and neuroprotective properties, the mechanisms by which Epo produces neuroprotection and the signal transduction systems regulated by Epo in the nervous system. (PMID:15053948)
• Results show no significant difference in erythropoietin values between non-anemic patients with liver disease and controls. (PMID:15112358)
• EPO is important for development of the brain and is neuroprotective, whereas it stimulates angiogenesis in the reproductive tract and possibly in other organs–REVIEW (PMID:15142852)
• Increased erythropoietin expression is associated with endometrial carcinoma (PMID:15160341)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	epoa	ENSDARG00000055163
danio_rerio	epob	ENSDARG00000100737
mus_musculus	Epo	ENSMUSG00000029711
rattus_norvegicus	Epo	ENSRNOG00000001412

Protein

Protein identifiers

Erythropoietin — P01588 (reviewed: P01588)

All UniProt accessions (2): P01588, G9JKG7

UniProt curated annotations — full annotation on UniProt →

Function. Hormone involved in the regulation of erythrocyte proliferation and differentiation and the maintenance of a physiological level of circulating erythrocyte mass. Binds to EPOR leading to EPOR dimerization and JAK2 activation thereby activating specific downstream effectors, including STAT1 and STAT3.

Subcellular location. Secreted.

Tissue specificity. Produced by kidney or liver of adult mammals and by liver of fetal or neonatal mammals.

Disease relevance. Microvascular complications of diabetes 2 (MVCD2) [MIM:612623] Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. Disease susceptibility is associated with variants affecting the gene represented in this entry. Erythrocytosis, familial, 5 (ECYT5) [MIM:617907] An autosomal dominant disorder characterized by elevated serum hemoglobin and hematocrit. Some patients have increased serum erythropoietin levels. The disease is caused by variants affecting the gene represented in this entry. Diamond-Blackfan anemia-like (DBAL) [MIM:617911] An autosomal recessive hematologic disease characterized by severe red cell hypoplastic anemia, selective absence of red cell precursors and progenitors seen on bone marrow biopsy, and increased serum erythropoietin. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the EPO/TPO family.

RefSeq proteins (1): NP_000790* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001323	EPO_TPO	Family
IPR003013	Erythroptn	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily
IPR019767	EPO/TPO_CS	Conserved_site

Pfam: PF00758

UniProt features (33 total): helix 9, sequence variant 8, glycosylation site 4, strand 4, sequence conflict 3, disulfide bond 2, signal peptide 1, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1EER	X-RAY DIFFRACTION	1.9
1CN4	X-RAY DIFFRACTION	2.8
1BUY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01588-F1	87.12	0.66

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (2): 34–188, 56–60

Glycosylation sites (4): 51, 65, 110, 153

Mutagenesis-validated functional residues (1):

Position	Phenotype
127	decreased erythrocyte proliferation; impaired epor dimerization following binding.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1234158	Regulation of gene expression by Hypoxia-inducible Factor
R-HSA-9006335	Signaling by Erythropoietin
R-HSA-9027276	Erythropoietin activates Phosphoinositide-3-kinase (PI3K)
R-HSA-9027277	Erythropoietin activates Phospholipase C gamma (PLCG)
R-HSA-9027283	Erythropoietin activates STAT5
R-HSA-9027284	Erythropoietin activates RAS

MSigDB gene sets: 282 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, HARRIS_HYPOXIA, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_RESPONSE_TO_CORTICOSTEROID, LFA1_Q6, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION

GO Biological Process (40): negative regulation of transcription by RNA polymerase II (GO:0000122), response to hypoxia (GO:0001666), acute-phase response (GO:0006953), signal transduction (GO:0007165), embryo implantation (GO:0007566), blood circulation (GO:0008015), positive regulation of cell population proliferation (GO:0008284), response to salt stress (GO:0009651), negative regulation of calcium ion transport into cytosol (GO:0010523), positive regulation of neuron projection development (GO:0010976), erythrocyte differentiation (GO:0030218), response to lipopolysaccharide (GO:0032496), myeloid cell apoptotic process (GO:0033028), response to vitamin A (GO:0033189), response to testosterone (GO:0033574), erythropoietin-mediated signaling pathway (GO:0038162), positive regulation of activated T cell proliferation (GO:0042104), hemoglobin biosynthetic process (GO:0042541), erythrocyte maturation (GO:0043249), response to estrogen (GO:0043627), positive regulation of neuron differentiation (GO:0045666), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of Ras protein signal transduction (GO:0046579), response to axon injury (GO:0048678), response to electrical stimulus (GO:0051602), response to hyperoxia (GO:0055093), positive regulation of ERK1 and ERK2 cascade (GO:0070374), response to interleukin-1 (GO:0070555), cellular hyperosmotic response (GO:0071474), response to dexamethasone (GO:0071548), cell surface receptor signaling pathway via STAT (GO:0097696), negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress (GO:1902219), negative regulation of erythrocyte apoptotic process (GO:1902251), regulation of transcription by RNA polymerase II (GO:0006357), apoptotic process (GO:0006915), response to stress (GO:0006950), response to nutrient (GO:0007584), negative regulation of myeloid cell apoptotic process (GO:0033033), negative regulation of apoptotic process (GO:0043066), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (5): cytokine activity (GO:0005125), erythropoietin receptor binding (GO:0005128), hormone activity (GO:0005179), protein kinase activator activity (GO:0030295), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cell surface (GO:0009986), cell body (GO:0044297)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by Erythropoietin	4
Cellular response to hypoxia	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to lipid	3
cellular anatomical structure	3
receptor ligand activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
response to stress	1
response to decreased oxygen levels	1
acute inflammatory response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
circulatory system process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
response to osmotic stress	1
regulation of calcium ion transport into cytosol	1
negative regulation of cytosolic calcium ion concentration	1
calcium ion transport into cytosol	1
negative regulation of calcium ion transmembrane transport	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
response to molecule of bacterial origin	1
response to oxygen-containing compound	1
apoptotic process	1
response to vitamin	1
response to ketone	1
cytokine-mediated signaling pathway	1
cellular response to erythropoietin	1
positive regulation of T cell proliferation	1
regulation of activated T cell proliferation	1

Protein interactions and networks

STRING

2907 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPO	EPOR	P19235	999
EPO	JAK2	O60674	974
EPO	IL3	P08700	955
EPO	THPO	P40225	925
EPO	CSF3	P09919	909
EPO	HAMP	P81172	904
EPO	EPAS1	Q99814	882
EPO	HIF1A	Q16665	877
EPO	CSF2	P04141	876
EPO	TFRC	P02786	858
EPO	EGLN1	Q9GZT9	851
EPO	MPL	P40238	839
EPO	KITLG	P21583	818
EPO	STAT5B	P51692	798
EPO	INS	P01308	787

IntAct

16 interactions, top by confidence:

A	B	Type	Score
EPOR	EPO	psi-mi:“MI:0407”(direct interaction)	0.610
EPO	EPOR	psi-mi:“MI:0915”(physical association)	0.610
EPO	EPHB4	psi-mi:“MI:0407”(direct interaction)	0.540
EPHB4	EPO	psi-mi:“MI:0407”(direct interaction)	0.540
EPO	EPHB4	psi-mi:“MI:0915”(physical association)	0.540
EPHB4	EPO	psi-mi:“MI:0915”(physical association)	0.540
EPO	MAN1A1	psi-mi:“MI:0915”(physical association)	0.500
EPO	EP300	psi-mi:“MI:0915”(physical association)	0.370
EPO	CFTR	psi-mi:“MI:0915”(physical association)	0.370
EPO	EPOR	psi-mi:“MI:0914”(association)	0.350
EPO	B4GALT5	psi-mi:“MI:0914”(association)	0.350
DOK2	EPO	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (22): EPOR (Two-hybrid), EPOR (Affinity Capture-MS), GINM1 (Affinity Capture-MS), EPO (Reconstituted Complex), EPO (Co-localization), EPO (Reconstituted Complex), EPO (Reconstituted Complex), EPOR (Affinity Capture-Luminescence), B4GALT6 (Affinity Capture-MS), PTPRS (Affinity Capture-MS), KIAA0319L (Affinity Capture-MS), MAN1A1 (Affinity Capture-MS), B4GALT5 (Affinity Capture-MS), EPOR (Reconstituted Complex), EPOR (Reconstituted Complex)

ESM2 similar proteins: A0A140LIA7, A0A1B0GTL2, A2VDX9, A3FFS8, A6NCS6, A8MVW0, K9M1U5, O43541, P01588, P03971, P03972, P07321, P07865, P0C7N4, P0DPE3, P13725, P27106, P29676, P33707, P33708, P33709, P48617, P49000, P49157, P53346, P79295, Q02011, Q0Z956, Q16619, Q1HCM0, Q28513, Q29RM6, Q5BLP8, Q5S1V9, Q60753, Q63086, Q65Z15, Q6H8S9, Q6H8T0, Q6H8T1

Diamond homologs: A3FFS8, P01588, P07321, P07865, P29676, P33707, P33708, P33709, P48617, P49157, Q0Z956, Q28513, Q2XNF5, Q4T554, Q5IGQ0, Q6H8S9, Q6H8T0, Q6H8T1, Q6H8T2, Q6JV22, Q867B1, Q9GKA2, P40225

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
HIF1A	“up-regulates quantity”	EPO	“transcriptional regulation”
EPO	“up-regulates quantity by expression”	HBB	“transcriptional regulation”
EPO	“up-regulates quantity by expression”	HBA1	“transcriptional regulation”
EPO	up-regulates	EPOR	binding
HIF1A	“up-regulates quantity by expression”	EPO	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

63 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	30
Likely benign	13
Benign	9

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
3906264	EPO, -252C-T, PROMOTER	Pathogenic
3906265	EPO, IVS1, T-C, -28	Pathogenic
3906266	EPO, IVS1, A-G, -26	Pathogenic
496593	NM_000799.4(EPO):c.33del (p.Trp11fs)	Pathogenic
496594	NM_000799.4(EPO):c.20del (p.Pro7fs)	Pathogenic
496595	NM_000799.4(EPO):c.530G>A (p.Arg177Gln)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1214 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:100722005:T:A	V68D	0.994
7:100722036:G:C	W78C	0.991
7:100722036:G:T	W78C	0.991
7:100723075:T:C	F175S	0.990
7:100723075:T:G	F175C	0.985
7:100722694:G:C	G93R	0.979
7:100723088:G:C	K179N	0.977
7:100723088:G:T	K179N	0.977
7:100722715:G:C	A100P	0.976
7:100722808:A:C	S131R	0.976
7:100722810:C:A	S131R	0.976
7:100722810:C:G	S131R	0.976
7:100723074:T:C	F175L	0.976
7:100723076:C:A	F175L	0.976
7:100723076:C:G	F175L	0.976
7:100723098:T:G	Y183D	0.975
7:100723084:G:A	G178E	0.974
7:100723083:G:A	G178R	0.973
7:100723083:G:C	G178R	0.973
7:100722008:C:G	P69R	0.970
7:100722034:T:A	W78R	0.966
7:100722034:T:C	W78R	0.966
7:100722698:T:C	L94P	0.966
7:100723084:G:T	G178V	0.966
7:100722024:T:A	N74K	0.965
7:100722024:T:G	N74K	0.965
7:100722008:C:A	P69Q	0.964
7:100722719:T:A	V101D	0.963
7:100723086:A:G	K179E	0.958
7:100722707:T:C	L97P	0.956

dbSNP variants (sampled 300 via entrez): RS1001117144 (7:100719744 T>C), RS1001251654 (7:100723270 A>G), RS1002119724 (7:100718607 G>A), RS1002253651 (7:100718736 C>A,T), RS1003573837 (7:100721619 C>T), RS1003790679 (7:100720712 C>A,T), RS1004479776 (7:100718696 A>G), RS1004580938 (7:100723707 TCTTGG>T), RS1005590776 (7:100722256 A>G), RS1005844562 (7:100719108 A>G,T), RS1005918224 (7:100718967 T>G), RS1007519774 (7:100720639 G>C), RS1008054609 (7:100719393 T>C), RS1008812599 (7:100724015 T>C), RS1009595668 (7:100719431 G>A)

Disease associations

OMIM: gene MIM:133170 | disease phenotypes: MIM:612623, MIM:617907, MIM:617911

GenCC curated gene-disease

Disease	Classification	Inheritance
erythrocytosis, familial, 5	Strong	Autosomal dominant
autosomal dominant secondary polycythemia	Supportive	Autosomal dominant
Diamond-Blackfan anemia-like	Limited	Autosomal recessive

Mondo (4): microvascular complications of diabetes, susceptibility to, 2 (MONDO:0012962), erythrocytosis, familial, 5 (MONDO:0033483), Diamond-Blackfan anemia-like (MONDO:0060662), (MONDO:0016599)

Orphanet (0):

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0001899	Increased hematocrit
HP:0001900	Increased circulating hemoglobin concentration
HP:0001901	Polycythemia
HP:0003593	Infantile onset
HP:0012410	Pure red cell aplasia
HP:0033074	Steroid-responsive anemia
HP:0033644	Elevated circulating erythropoietin concentration

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST000500_3	Other erythrocyte phenotypes	1.000000e-09
GCST001725_95	Inflammatory bowel disease	2.000000e-13
GCST004601_102	Red blood cell count	2.000000e-92
GCST004604_124	Hematocrit	4.000000e-12
GCST004604_125	Hematocrit	4.000000e-32
GCST004615_51	Hemoglobin concentration	1.000000e-10
GCST005028_3	Pursuit maintenance gain in psychotic disorders	1.000000e-07
GCST006585_2693	Blood protein levels	2.000000e-06
GCST009466_2	Hematocrit	6.000000e-09
GCST009467_4	Hemoglobin levels	3.000000e-08
GCST010002_259	Refractive error	3.000000e-16
GCST010083_119	Hemoglobin levels	2.000000e-73
GCST010245_28	LDL cholesterol levels	5.000000e-09
GCST90002383_430	Hematocrit	8.000000e-56
GCST90002383_434	Hematocrit	8.000000e-44
GCST90002383_435	Hematocrit	1.000000e-89
GCST90002384_159	Hemoglobin	3.000000e-36
GCST90002384_160	Hemoglobin	1.000000e-78
GCST90002400_44	Plateletcrit	5.000000e-09
GCST90002403_586	Red blood cell count	1.000000e-46
GCST90002403_587	Red blood cell count	3.000000e-55
GCST90020029_879	Waist circumference adjusted for body mass index	8.000000e-09
GCST90020029_880	Waist circumference adjusted for body mass index	3.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0008433	pursuit maintenance gain measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0007985	platelet crit
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5837 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

103 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Oxygen	affects binding, increases reaction, affects reaction, decreases expression, decreases reaction (+3 more)	11
cobaltous chloride	decreases reaction, increases expression, affects expression, increases reaction	9
Benzo(a)pyrene	decreases expression, increases expression, increases methylation, affects methylation	4
Amphotericin B	affects binding, decreases reaction, increases expression, decreases expression	3
Cisplatin	decreases reaction, increases expression, decreases abundance, increases activity, decreases response to substance (+1 more)	3
Cobalt	decreases reaction, increases expression	3
Quercetin	decreases expression, affects cotreatment, decreases reaction, increases expression	3
Ribavirin	affects cotreatment, affects expression, increases expression	3
bisphenol A	affects expression, decreases reaction, increases expression	2
formononetin	increases expression	2
sodium arsenate	increases abundance, increases secretion, decreases reaction, increases expression, decreases expression (+1 more)	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects cotreatment, increases expression, decreases reaction, increases abundance	2
7,3’-dihydroxy-4’-methoxyisoflavone	increases expression	2
calycosin-7-O-beta-D-glucoside	increases expression	2
Enalapril	decreases expression	2
Etoposide	decreases reaction, increases activity, affects cotreatment, increases response to substance	2
Clioquinol	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression	2
aristolochic acid I	increases expression	1
cremophor EL	decreases response to substance	1
OTX015	decreases expression	1
mivebresib	decreases expression	1
dihydrotanshinone I	increases expression, decreases reaction	1
tempol	increases expression, decreases reaction	1
sapropterin	decreases abundance, decreases reaction	1
baicalein	increases expression	1
emulphogene BC 720	increases expression	1
Nonidet P-40	decreases expression	1
IMOL S-140	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5130506	Binding	Irreversible inhibition of EPO (unknown origin) incubated with compound followed by drug washing and later treated with H2O2 for enzyme reactivation by chemiluminescence assay	Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction. — J Med Chem

Cellosaurus cell lines

10 cell lines: 5 transformed cell line, 4 spontaneously immortalized cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_6369	BHK21-pcDNA3.1-HC	Spontaneously immortalized cell line	Male
CVCL_A8SQ	CHO-gmt4D-EPO-GnT I	Spontaneously immortalized cell line	Female
CVCL_B0H2	Sp2/0-Ag14 hEPO	Cancer cell line	Female
CVCL_B5T3	RS-1C9	Transformed cell line	Male
CVCL_D9WU	Ubigene HTR-8/SVneo EPO KO	Transformed cell line	Sex unspecified
CVCL_JZ95	CHO-ADLE	Transformed cell line	Female
CVCL_JZ96	CHO-AFLE	Transformed cell line	Female
CVCL_RQ72	BHK-21A EPO40	Spontaneously immortalized cell line	Male
CVCL_RQ73	BHK-21A EPO40-ST6NI	Spontaneously immortalized cell line	Male
CVCL_VU03	CHO B8-300	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.