Hyperlipoproteinemia type 3

Summary

Hyperlipoproteinemia type 3 (MONDO:0018473) is a disease caused by APOE (GenCC Strong), with 2 cohort genes and 5 clinical trials. Top therapeutic interventions include atorvastatin, evinacumab, and fenofibrate.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Causal gene: APOE (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 34
• Phenotypes (HPO): 26
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Worldwide	Validated
Point prevalence	1-9 / 100 000	7.8	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000951	Abnormality of the skin	Very frequent (80-99%)
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0003124	Hypercholesterolemia	Very frequent (80-99%)
HP:0003141	Increased LDL cholesterol concentration	Very frequent (80-99%)
HP:0003233	Decreased HDL cholesterol concentration	Very frequent (80-99%)
HP:0000660	Lipemia retinalis	Frequent (30-79%)
HP:0000819	Diabetes mellitus	Frequent (30-79%)
HP:0001013	Eruptive xanthomas	Frequent (30-79%)
HP:0001084	Corneal arcus	Frequent (30-79%)
HP:0001114	Xanthelasma	Frequent (30-79%)
HP:0001397	Hepatic steatosis	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002635	Atheromatosis	Frequent (30-79%)
HP:0010874	Tendon xanthomatosis	Frequent (30-79%)
HP:0025530	Xanthomas of the palmar creases	Frequent (30-79%)
HP:0031290	Tuberous xanthoma	Frequent (30-79%)
HP:0000799	Renal steatosis	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0001681	Angina pectoris	Occasional (5-29%)
HP:0001735	Acute pancreatitis	Occasional (5-29%)
HP:0001997	Gout	Occasional (5-29%)
HP:0004943	Accelerated atherosclerosis	Occasional (5-29%)
HP:0004950	Peripheral arterial stenosis	Occasional (5-29%)
HP:0005181	Premature coronary artery atherosclerosis	Occasional (5-29%)
HP:0012397	Aortic atherosclerosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperlipoproteinemia type 3
Mondo ID	MONDO:0018473
OMIM	617347
Orphanet	412
DOID	DOID:3145
SNOMED CT	398796005
UMLS	C0020479
MedGen	9364
GARD	0006703
MedDRA	10060751
Is cancer (heuristic)	no

Also known as: Broad beta disease · Broad-betalipoproteinemia · dysbetalipoproteinemia · dyslipidaemia type 3 · dyslipidemia type 3 · familial dysbetalipoproteinemia · familial hyperlipoproteinemia type 3 · HLP type 3 · hyperlipidemia type 3 · hyperlipoproteinemia type III · remnant disease · remnant removal disease

Data availability: 34 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › familial hyperlipidemia › hyperlipoproteinemia type 3

Related subtypes (9): familial hypercholesterolemia, cholesterol-ester transfer protein deficiency, hyperlipidemia, familial combined, LPL related, hyperlipoproteinemia type V, familial apolipoprotein C-II deficiency, familial lipoprotein lipase deficiency, hyperlipidemia, combined, 2, hyperlipidemia due to hepatic triglyceride lipase deficiency, hyperlipoproteinemia, type 1D

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

34 retrieved; paginated sample, class counts are floors:

9 pathogenic, 7 uncertain significance, 7 conflicting classifications of pathogenicity, 5 likely pathogenic, 2 likely benign, 1 drug response, 1 pathogenic/likely pathogenic, 1 not provided, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
441264	NM_000041.3(APOE):c.[487C>T;91G>A]		Pathogenic	no assertion criteria provided
441265	NM_000041.3(APOE):c.[526C>T;725G>A]		Pathogenic	no assertion criteria provided
441267	NM_000041.3(APOE):c.[388T>C;805C>G]		Pathogenic	no assertion criteria provided
17852	NM_000041.4(APOE):c.237-2A>G	APOE	Pathogenic	no assertion criteria provided
17853	NM_000041.4(APOE):c.415_435dup (p.Glu139_Gly145dup)	APOE	Pathogenic	no assertion criteria provided
17857	NM_000041.4(APOE):c.490A>G (p.Lys164Glu)	APOE	Pathogenic	no assertion criteria provided
17861	NM_000041.4(APOE):c.146del (p.Gly49fs)	APOE	Pathogenic	no assertion criteria provided
17880	NM_000041.4(APOE):c.127C>T (p.Arg43Cys)	APOE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
972902	NM_000527.5(LDLR):c.1010_1013dup (p.Cys338Ter)	LDLR	Pathogenic	criteria provided, multiple submitters, no conflicts
972903	NM_000527.5(LDLR):c.2312-2A>G	LDLR	Pathogenic	criteria provided, multiple submitters, no conflicts
1341575	NM_000041.4(APOE):c.548G>C (p.Gly183Ala)	APOE	Likely pathogenic	criteria provided, single submitter
17850	NM_000041.4(APOE):c.460C>A (p.Arg154Ser)	APOE	Likely pathogenic	criteria provided, multiple submitters, no conflicts
17862	NM_000041.4(APOE):c.683G>A (p.Trp228Ter)	APOE	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293233	NM_000041.4(APOE):c.461G>A (p.Arg154His)	APOE	Likely pathogenic	criteria provided, single submitter
487346	NM_000041.4(APOE):c.478C>T (p.Arg160Cys)	APOE	Likely pathogenic	criteria provided, single submitter
17848	NM_000041.2(APOE):c.526C>T (p.Arg176Cys)	APOE	drug response	reviewed by expert panel
1722323	NM_000041.4(APOE):c.-24+82G>A	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17851	NM_000041.4(APOE):c.487C>T (p.Arg163Cys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17865	NM_000041.4(APOE):c.488G>A (p.Arg163His)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17876	NM_000041.4(APOE):c.940A>C (p.Ser314Arg)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803815	NM_000041.4(APOE):c.31A>G (p.Thr11Ala)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3572888	NM_000041.4(APOE):c.460C>T (p.Arg154Cys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
440842	NM_000041.4(APOE):c.91G>A (p.Glu31Lys)	APOE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1315806	NM_000041.4(APOE):c.688G>A (p.Glu230Lys)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1764810	NM_000041.4(APOE):c.882G>T (p.Trp294Cys)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
3066201	NM_000041.4(APOE):c.327dup (p.Arg110fs)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
478872	NM_000041.4(APOE):c.761T>A (p.Val254Glu)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
478884	NM_000041.4(APOE):c.805C>G (p.Arg269Gly)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
478904	NM_000041.4(APOE):c.434G>A (p.Gly145Asp)	APOE	Uncertain significance	criteria provided, multiple submitters, no conflicts
917851	NM_000041.4(APOE):c.422A>G (p.Gln141Arg)	APOE	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
APOE	Strong	Autosomal dominant	hyperlipoproteinemia type 3	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia
LDLR	Orphanet:391665	Homozygous familial hypercholesterolemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOE	HGNC:613	ENSG00000130203	P02649	Apolipoprotein E	gencc,clinvar
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOE	Apolipoprotein E	APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids.
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOE	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
adrenal tissue	1
lower lobe of lung	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOE	267	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland cortex
LDLR	281	ubiquitous	marker	adrenal tissue, lower lobe of lung, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793
LDLR	1,426

Intra-cohort edges

A	B	Sources
APOE	LDLR	intact

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LDLR	P01130	36
APOE	P02649	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chylomicron clearance	2	2284.0×	6e-06	APOE, LDLR
Plasma lipoprotein clearance	2	475.8×	8e-05	APOE, LDLR
Metabolism of fat-soluble vitamins	2	380.7×	8e-05	APOE, LDLR
Visual phototransduction	2	259.6×	1e-04	APOE, LDLR
Retinoid metabolism and transport	2	248.3×	1e-04	APOE, LDLR
Plasma lipoprotein assembly, remodeling, and clearance	2	228.4×	1e-04	APOE, LDLR
Metabolism of vitamins and cofactors	2	116.5×	4e-04	APOE, LDLR
Sensory Perception	2	95.2×	5e-04	APOE, LDLR
Vesicle-mediated transport	2	34.8×	0.003	APOE, LDLR
Chylomicron assembly	1	571.0×	0.005	APOE
Chylomicron remodeling	1	571.0×	0.005	APOE
HDL remodeling	1	571.0×	0.005	APOE
Transport of small molecules	2	25.1×	0.005	APOE, LDLR
Plasma lipoprotein assembly	1	356.9×	0.008	APOE
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	317.2×	0.008	APOE
Scavenging by Class A Receptors	1	300.5×	0.008	APOE
Binding and Uptake of Ligands by Scavenger Receptors	1	271.9×	0.008	APOE
LDL clearance	1	271.9×	0.008	LDLR
Plasma lipoprotein remodeling	1	237.9×	0.008	APOE
NR1H2 and NR1H3-mediated signaling	1	196.9×	0.010	APOE
Nuclear signaling by ERBB4	1	173.0×	0.010	APOE
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	154.3×	0.011	APOE
Signaling by ERBB4	1	135.9×	0.012	APOE
Metabolism	2	11.6×	0.012	APOE, LDLR
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.027	LDLR
Amyloid fiber formation	1	51.4×	0.027	APOE
Signaling by Nuclear Receptors	1	51.0×	0.027	APOE
Post-translational protein phosphorylation	1	50.1×	0.027	APOE
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.030	APOE
Clathrin-mediated endocytosis	1	42.6×	0.030	LDLR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
high-density lipoprotein particle clearance	2	2407.4×	6e-06	APOE, LDLR
lipoprotein catabolic process	2	2407.4×	6e-06	APOE, LDLR
regulation of protein metabolic process	2	2106.5×	6e-06	APOE, LDLR
negative regulation of protein metabolic process	2	2106.5×	6e-06	APOE, LDLR
response to caloric restriction	2	1532.0×	9e-06	APOE, LDLR
negative regulation of amyloid fibril formation	2	1296.3×	1e-05	APOE, LDLR
regulation of cholesterol metabolic process	2	1123.5×	1e-05	APOE, LDLR
artery morphogenesis	2	674.1×	3e-05	APOE, LDLR
long-term memory	2	421.3×	7e-05	APOE, LDLR
receptor-mediated endocytosis	2	221.7×	2e-04	APOE, LDLR
cholesterol metabolic process	2	195.9×	3e-04	APOE, LDLR
cholesterol homeostasis	2	156.0×	4e-04	APOE, LDLR
lipid transport involved in lipid storage	1	8426.0×	9e-04	APOE
maintenance of location in cell	1	8426.0×	9e-04	APOE
intermediate-density lipoprotein particle clearance	1	8426.0×	9e-04	APOE
positive regulation of lipid transport across blood-brain barrier	1	8426.0×	9e-04	APOE
regulation of cellular response to very-low-density lipoprotein particle stimulus	1	8426.0×	9e-04	APOE
regulation of phosphatidylcholine catabolic process	1	4213.0×	0.001	LDLR
triglyceride-rich lipoprotein particle clearance	1	4213.0×	0.001	APOE
receptor-mediated endocytosis involved in cholesterol transport	1	4213.0×	0.001	LDLR
regulation of amyloid-beta clearance	1	4213.0×	0.001	APOE
regulation of amyloid fibril formation	1	4213.0×	0.001	APOE
negative regulation of gene expression	2	69.1×	0.001	APOE, LDLR
positive regulation of low-density lipoprotein particle receptor catabolic process	1	2808.7×	0.002	APOE
negative regulation of astrocyte activation	1	2808.7×	0.002	LDLR
plasma lipoprotein particle clearance	1	2106.5×	0.002	LDLR
negative regulation of triglyceride metabolic process	1	2106.5×	0.002	APOE
positive regulation of phospholipid efflux	1	2106.5×	0.002	APOE
regulation of behavioral fear response	1	2106.5×	0.002	APOE
negative regulation of receptor recycling	1	1685.2×	0.002	LDLR

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LDLR	NILOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LDLR	1	4
APOE	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NILOTINIB	4	LDLR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LDLR	55	Binding:54, Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
NILOTINIB	4	LDLR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LDLR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	APOE

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
APOE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
Not specified	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03811223	PHASE4	UNKNOWN	Effects of Evolocumab Versus Placebo Added to Standard Lipid-lowering Therapy on Fasting and Post Fat Load Lipids in Patients With Familial Dysbetalipoproteinemia
NCT00145431	PHASE3	TERMINATED	Study To Evaluate The Effect Of Torcetrapib/Atorvastatin In Subjects With A Genetic Cholesterol Disorder.
NCT00214604	PHASE3	COMPLETED	Type III Dysbetalipoproteinemia
NCT01760265	Not specified	UNKNOWN	DARK STUDY DysbetalipoproteinemiA and atheRoma Risk
NCT06500598	Not specified	APPROVED_FOR_MARKETING	Compassionate Use of Evinacumab

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ATORVASTATIN	4	1
EVINACUMAB	4	1
FENOFIBRATE	4	1
PRAVASTATIN	4	1
TORCETRAPIB	3	1