HPR

Summary

HPR (haptoglobin-related protein, HGNC:5156) is a protein-coding gene on chromosome 16q22.2, encoding Haptoglobin-related protein (P00739). Primate-specific plasma protein associated with apolipoprotein L-I (apoL-I)-containing high-density lipoprotein (HDL).

This gene encodes a haptoglobin-related protein that binds hemoglobin as efficiently as haptoglobin. Unlike haptoglobin, plasma concentration of this protein is unaffected in patients with sickle cell anemia and extensive intravascular hemolysis, suggesting a difference in binding between haptoglobin-hemoglobin and haptoglobin-related protein-hemoglobin complexes to CD163, the hemoglobin scavenger receptor. This protein may also be a clinically important predictor of recurrence of breast cancer.

Source: NCBI Gene 3250 — RefSeq curated summary.

At a glance

• GWAS associations: 54
• Clinical variants (ClinVar): 87 total
• MANE Select transcript: NM_020995

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5156
Approved symbol	HPR
Name	haptoglobin-related protein
Location	16q22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000261701
Ensembl biotype	protein_coding
OMIM	140210
Entrez	3250

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000540303, ENST00000561690, ENST00000566168, ENST00000649683, ENST00000892521

RefSeq mRNA: 2 — MANE Select: NM_020995 NM_001384360, NM_020995

CCDS: CCDS42193

Canonical transcript exons

ENST00000540303 — 5 exons

Exon	Start	End
ENSE00002468192	72075145	72075219
ENSE00002534765	72074284	72074385
ENSE00002597546	72063226	72063260
ENSE00002608980	72076303	72077246
ENSE00003476606	72073892	72073977

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 99.03.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2210 / max 101.3481, expressed in 67 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154965	0.1308	44
154967	0.0618	16
154966	0.0283	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.03	gold quality
liver	UBERON:0002107	98.16	gold quality
apex of heart	UBERON:0002098	96.50	gold quality
heart left ventricle	UBERON:0002084	95.19	gold quality
cardiac ventricle	UBERON:0002082	94.75	gold quality
heart right ventricle	UBERON:0002080	88.84	gold quality
heart	UBERON:0000948	87.92	gold quality
right atrium auricular region	UBERON:0006631	86.13	gold quality
cardiac atrium	UBERON:0002081	84.48	gold quality
left ventricle myocardium	UBERON:0006566	84.15	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.87	gold quality
myocardium	UBERON:0002349	79.55	gold quality
putamen	UBERON:0001874	78.37	gold quality
caudate nucleus	UBERON:0001873	77.86	gold quality
tibial nerve	UBERON:0001323	76.48	gold quality
amygdala	UBERON:0001876	75.63	gold quality
prefrontal cortex	UBERON:0000451	75.04	gold quality
substantia nigra	UBERON:0002038	75.01	gold quality
nucleus accumbens	UBERON:0001882	74.74	gold quality
left coronary artery	UBERON:0001626	74.52	gold quality
anterior cingulate cortex	UBERON:0009835	74.06	gold quality
cingulate cortex	UBERON:0003027	74.02	gold quality
right frontal lobe	UBERON:0002810	73.08	gold quality
midbrain	UBERON:0001891	72.70	gold quality
coronary artery	UBERON:0001621	72.68	gold quality
hypothalamus	UBERON:0001898	72.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	71.59	gold quality
lateral globus pallidus	UBERON:0002476	70.91	gold quality
frontal cortex	UBERON:0001870	70.62	gold quality
cardiac muscle of right atrium	UBERON:0003379	70.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3

miRNA regulators (miRDB)

3 targeting HPR, 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-6715B-3P	98.80	68.07	1204
HSA-MIR-512-5P	97.47	66.48	591
HSA-MIR-1247-5P	85.92	61.07	65

Literature-anchored findings (GeneRIF, showing 13)

• No trypanosome lytic activity in the sera of mice producing human haptoglobin-related protein (PMID:11814582)
• recombinant Hpr binds hemoglobin as efficiently as haptoglobin (PMID:16778136)
• apoL-I is responsible for the trypanolytic activity of normal human serum, whereas Hpr allows fast uptake of the carrier HDL particles in trypanolysis (PMID:17360487)
• Infection by Trypanosoma brucei brucei causes hemolysis that triggers activation of trypanosome lytic factor by formation of haptoglobin-related protein-hemoglobin complexes, enhancing binding, trypanolytic activity, and clearance of parasites. (PMID:17845074)
• at low pH. Trypanosome lytic factor, apoL-1, and apoA-1 exhibit specificity for anionic membranes, whereas Hpr permeabilizes both anionic and zwitterionic membranes. (PMID:19324878)
• show that trypanosome lytic factor-1 resistance in Trypanosoma brucei brucei is caused by reduced expression of the Hp/Hb receptor gene. (PMID:20805508)
• Our analysis illustrates the complex interplay between functions and haplotypes of adjacent genes, environmental context and natural selection, and offers insights into potential use of haptoglobin or haptoglobin-related protein as therapeutic agents. (PMID:22433445)
• Data indicate that haptoglobin-related protein (Hpr) is presented at the surface of hepG2 cells. (PMID:25037218)
• the haptoglobin (HP) rs8062041 appeared to be protective against African Trypanosomiasis; HPR is adjacent to HP and is a component of the Trypanolytic factor; the HP and HPR locus is duplicated in some people; the rs8062041 variant may be associated with this duplication and it is possible that increased production of HPR is the cause of protection associated with rs806204 (PMID:29077717)
• These results indicate that HPR is a potential serologic biomarker which can differentiate between bacterial pneumonia and nonbacterial pneumonia. Detection of serum HPR might be useful for clinical diagnosis. (PMID:29785832)
• Haptoglobin polymorphisms in Latin American populations. (PMID:32792581)
• Haptoglobin-related protein in human plasma correlates to haptoglobin concentrations and phenotypes. (PMID:36129375)
• Haptoglobin-Related Protein without Signal Peptide as Biomarker of Renal Salt Wasting in Hyponatremia, Hyponatremia-Related Diseases and as New Syndrome in Alzheimer’s Disease. (PMID:37189385)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hp	ENSMUSG00000031722
rattus_norvegicus	Hp	ENSRNOG00000014964
drosophila_melanogaster	CG31266	FBGN0051266
drosophila_melanogaster	CG31267	FBGN0051267

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1RL (ENSG00000139178), C1R (ENSG00000159403), KLKB1 (ENSG00000164344), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), CFI (ENSG00000205403), PRSS51 (ENSG00000253649), HP (ENSG00000257017)

Protein

Protein identifiers

Haptoglobin-related protein — P00739 (reviewed: P00739)

All UniProt accessions (3): A0A3B3ISM1, J3KTC3, P00739

UniProt curated annotations — full annotation on UniProt →

Function. Primate-specific plasma protein associated with apolipoprotein L-I (apoL-I)-containing high-density lipoprotein (HDL). This HDL particle, termed trypanosome lytic factor-1 (TLF-1), mediates human innate immune protection against many species of African trypanosomes. Binds hemoglobin with high affinity and may contribute to the clearance of cell-free hemoglobin to allow hepatic recycling of heme iron.

Subcellular location. Secreted.

Tissue specificity. In adult liver the amount of HPR mRNA is at the lower limit of detection, therefore the extent of its expression is at most less than 1000-fold that of the HP1F gene. No HPR mRNA can be detected in fetal liver. Expressed in Hep-G2 and leukemia MOLT-4 cell lines.

Domain organisation. The uncleaved signal sequence interacts with HDL fluid lipids and mediates incorporation into the HDL particle.

Similarity. Belongs to the peptidase S1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P00739-1	1	yes
P00739-2	2

RefSeq proteins (2): NP_001371289, NP_066275* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR008292	Haptoglobin	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR043504

Pfam: PF00089

UniProt features (15 total): sequence variant 7, domain 2, disulfide bond 2, chain 1, signal peptide 1, sequence conflict 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00739-F1	87.79	0.77

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): 251–282, 293–323

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2168880	Scavenging of heme from plasma

MSigDB gene sets: 58 (showing top): chr16q22, GNF2_HPN, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MODULE_66, GOBP_PROTEIN_MATURATION, GNF2_LCAT, GNF2_HPX, MODULE_88, MODULE_11, GOBP_ZYMOGEN_ACTIVATION, MODULE_104, GOCC_HIGH_DENSITY_LIPOPROTEIN_PARTICLE, GOCC_BLOOD_MICROPARTICLE, MODULE_55, GOBP_PROTEOLYSIS

GO Biological Process (2): zymogen activation (GO:0031638), proteolysis (GO:0006508)

GO Molecular Function (2): serine-type endopeptidase activity (GO:0004252), hemoglobin binding (GO:0030492)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), spherical high-density lipoprotein particle (GO:0034366), extracellular exosome (GO:0070062), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Binding and Uptake of Ligands by Scavenger Receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein processing	1
protein metabolic process	1
endopeptidase activity	1
serine-type peptidase activity	1
protein binding	1
high-density lipoprotein particle	1
extracellular vesicle	1
extracellular region	1

Protein interactions and networks

STRING

994 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPR	APOL1	O14791	998
HPR	APOA1	P02647	992
HPR	CD163	Q86VB7	845
HPR	PON1	P27169	833
HPR	APOA2	P02652	705
HPR	TBPL1	P62380	692
HPR	TCF3	P15883	667
HPR	SERPINA1	P01009	613
HPR	TF	P02787	572
HPR	C3	P01024	571
HPR	CP	P00450	559
HPR	A2M	P01023	549
HPR	HPX	P02790	531
HPR	CRP	P02741	481
HPR	APOL5	Q9BWW9	478

IntAct

11 interactions, top by confidence:

A	B	Type	Score
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
GNG8	POTEF	psi-mi:“MI:0914”(association)	0.350
HPR	HP	psi-mi:“MI:0914”(association)	0.350
ZNF492	HPR	psi-mi:“MI:0914”(association)	0.350
PHF11	A2ML1	psi-mi:“MI:0914”(association)	0.350
MATN2	IGLL5	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (22): HPR (Reconstituted Complex), TCP1 (Affinity Capture-MS), HPR (Affinity Capture-MS), CCT6B (Affinity Capture-MS), HP (Affinity Capture-MS), CCT6A (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), HPR (Affinity Capture-MS), HPR (Affinity Capture-Western), HPR (Affinity Capture-MS), HPR (Affinity Capture-MS), HPR (Affinity Capture-MS), HPR (Proximity Label-MS), HPR (Affinity Capture-MS)

ESM2 similar proteins: A0A182C2Z2, A0A1S4GMJ4, A6MFK7, A6MFK8, B5G6G5, O01887, O35086, P00739, P00740, P00741, P05156, P15120, P16294, P16296, P19007, P19540, P29598, P81428, P82807, P83370, Q17800, Q1L658, Q1L659, Q27081, Q27083, Q28801, Q3UQ41, Q4QXT9, Q56VR3, Q58L93, Q58L94, Q58L95, Q58L96, Q5QSK2, Q5R5A4, Q60574, Q61129, Q62558, Q66TN7, Q6SA95

Diamond homologs: A0A1D5NSM8, A2AVA0, B6D985, B6E141, O35086, P00736, P00738, P00739, P00743, P06866, P09871, P15156, P19006, P19007, P43430, P50417, P57727, P70375, P80010, Q0VCX1, Q28801, Q2TBU0, Q3UZ09, Q4R577, Q5R1W3, Q5R544, Q5R5F6, Q5VAN1, Q60574, Q61646, Q62558, Q69DK8, Q6IE14, Q6IE64, Q6P6T1, Q7SZE1, Q8CFG8, Q8CFG9, Q8CG14, Q8CG16

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	66
Likely benign	14
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

845 predictions. Top by Δscore:

Variant	Effect	Δscore
16:72073890:A:AG	acceptor_gain	1.0000
16:72073891:G:GG	acceptor_gain	1.0000
16:72074281:CAGAT:C	acceptor_loss	1.0000
16:72074282:A:AG	acceptor_gain	1.0000
16:72074282:AGA:A	acceptor_loss	1.0000
16:72074282:AGAT:A	acceptor_gain	1.0000
16:72074283:G:GG	acceptor_gain	1.0000
16:72074283:GA:G	acceptor_gain	1.0000
16:72074283:GAT:G	acceptor_gain	1.0000
16:72074283:GATG:G	acceptor_gain	1.0000
16:72074283:GATGA:G	acceptor_gain	1.0000
16:72074348:GT:G	donor_gain	1.0000
16:72074382:GATG:G	donor_gain	1.0000
16:72074384:TGG:T	donor_loss	1.0000
16:72074386:G:GG	donor_gain	1.0000
16:72074386:GTAA:G	donor_loss	1.0000
16:72074387:T:A	donor_loss	1.0000
16:72076302:GTAT:G	acceptor_gain	1.0000
16:72070764:A:G	donor_gain	0.9900
16:72071694:G:GA	donor_gain	0.9900
16:72071728:G:GG	donor_gain	0.9900
16:72073891:GT:G	acceptor_gain	0.9900
16:72074279:T:A	acceptor_gain	0.9900
16:72074384:TG:T	donor_gain	0.9900
16:72074385:GG:G	donor_gain	0.9900
16:72075144:GGA:G	acceptor_gain	0.9900
16:72076301:A:AG	acceptor_gain	0.9900
16:72076302:G:GA	acceptor_gain	0.9900
16:72076302:GT:G	acceptor_gain	0.9900
16:72063260:GGT:G	donor_loss	0.9800

AlphaMissense

2285 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:72076383:T:A	W117R	0.985
16:72076383:T:C	W117R	0.985
16:72076385:G:C	W117C	0.985
16:72076385:G:T	W117C	0.985
16:72076446:T:A	W138R	0.983
16:72076446:T:C	W138R	0.983
16:72076377:T:C	F115L	0.982
16:72076379:T:A	F115L	0.982
16:72076379:T:G	F115L	0.982
16:72077054:G:C	W340C	0.979
16:72077054:G:T	W340C	0.979
16:72076712:G:C	W226C	0.978
16:72076712:G:T	W226C	0.978
16:72076450:T:C	L139P	0.975
16:72076606:T:C	L191P	0.974
16:72076448:G:C	W138C	0.969
16:72076448:G:T	W138C	0.969
16:72076929:A:C	S299R	0.969
16:72076931:T:A	S299R	0.969
16:72076931:T:G	S299R	0.969
16:72076989:T:C	F319L	0.967
16:72076991:T:A	F319L	0.967
16:72076991:T:G	F319L	0.967
16:72074349:T:A	C53S	0.961
16:72074350:G:C	C53S	0.961
16:72075210:T:A	C87S	0.957
16:72075211:G:C	C87S	0.957
16:72076656:T:A	C208S	0.957
16:72076657:G:C	C208S	0.957
16:72076965:T:A	W311R	0.956

dbSNP variants (sampled 300 via entrez): RS1000101977 (16:72073170 T>A,C,G), RS1000154294 (16:72072906 T>C), RS1000352952 (16:72067336 A>T), RS1000683136 (16:72062711 A>G), RS1000761766 (16:72062253 C>G,T), RS1001195469 (16:72061624 A>T), RS1001310303 (16:72061481 A>G), RS1001342363 (16:72067394 T>G), RS1001855631 (16:72067652 T>C), RS1002228490 (16:72073652 C>G,T), RS1002565306 (16:72074717 C>G,T), RS1003120903 (16:72069037 G>A), RS1003340577 (16:72070056 C>T), RS1003706853 (16:72064079 T>C,G), RS1003774565 (16:72077731 G>A,T)

Disease associations

OMIM: gene MIM:140210 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

54 associations (top):

Study	Trait	p-value
GCST000759_13	LDL cholesterol	2.000000e-22
GCST000760_22	Cholesterol, total	3.000000e-24
GCST001276_4	Liver enzyme levels (alkaline phosphatase)	5.000000e-09
GCST001639_4	Metabolite levels	1.000000e-36
GCST002221_59	Cholesterol, total	7.000000e-41
GCST002222_29	LDL cholesterol	4.000000e-41
GCST002896_11	Cholesterol, total	3.000000e-23
GCST002898_10	LDL cholesterol	2.000000e-20
GCST003214_12	Cholesterol, total	7.000000e-07
GCST003216_6	LDL cholesterol	8.000000e-07
GCST004209_9	Cholesterol, total	7.000000e-09
GCST004233_35	LDL cholesterol levels	5.000000e-45
GCST004233_63	LDL cholesterol levels	2.000000e-06
GCST004235_20	Total cholesterol levels	2.000000e-44
GCST004235_3	Total cholesterol levels	2.000000e-06
GCST008074_124	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-10
GCST008074_148	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-11
GCST008077_13	LDL cholesterol levels	4.000000e-11
GCST008077_36	LDL cholesterol levels	2.000000e-12
GCST008077_54	LDL cholesterol levels	7.000000e-24
GCST008078_148	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-43
GCST008078_55	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	8.000000e-54
GCST008078_81	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-10
GCST008078_93	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-06
GCST008079_114	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-45
GCST008079_28	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-06
GCST008079_40	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-59
GCST008079_88	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-12
GCST008083_110	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-13
GCST008083_3	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	4.000000e-12

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0004723	coronary artery calcification
EFO:0004530	triglyceride measurement
EFO:0004329	alcohol drinking
EFO:0006925	lipoprotein A measurement
EFO:0004348	hematocrit
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2000999	HPR		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases methylation	4
Benzo(a)pyrene	affects methylation, decreases expression	3
Cyclosporine	decreases expression, affects expression	3
Tetrachlorodibenzodioxin	decreases expression	2
Asian ginseng	decreases expression, decreases reaction	1
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
bisphenol A	affects expression	1
sulforaphane	increases expression	1
sodium arsenite	decreases expression	1
potassium bromate	decreases expression	1
ochratoxin A	affects expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
Acetaminophen	increases expression	1
Azathioprine	decreases expression	1
Cadmium	affects binding	1
Copper	affects binding	1
Dexamethasone	increases expression	1
Diethylhexyl Phthalate	decreases expression, decreases reaction	1
Doxorubicin	decreases expression	1
Methotrexate	decreases expression	1
Nickel	affects binding	1
Quercetin	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression, decreases methylation	1
Zinc	affects binding	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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