Hyperlipoproteinemia

Summary

Hyperlipoproteinemia (MONDO:0037748) is a disease with 3 cohort genes and 28 clinical trials. Top therapeutic interventions include mipomersen, rosuvastatin, and fenofibrate.

At a glance

• Cohort genes: 3
• ClinVar variants: 3
• Clinical trials: 28

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperlipoproteinemia
Mondo ID	MONDO:0037748
MeSH	D006951
NCIT	C34709
UMLS	C0020476
MedGen	9363
Is cancer (heuristic)	no

Also known as: hyperlipoproteinemia

Data availability: 3 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › hyperlipoproteinemia

Related subtypes (36): glutaric aciduria, mineral metabolism disease, xanthinuria, chondrocalcinosis, ochronosis disorder, glucose metabolism disease, diabetic kidney disease, xanthoma, diabetic retinopathy, hypertriglyceridemia, gout, lactic acidosis, acquired metabolic disease, lipodystrophy, developmental anomaly of metabolic origin, dopa-responsive dystonia, hypoalphalipoproteinemia, steroid dehydrogenase deficiency-dental anomalies syndrome, inborn errors of metabolism, vitamin B12 deficiency, proteostasis deficiencies, hyperlipidemia, disorder of GPI anchor biosynthesis, bilirubin metabolism disease, carbohydrate metabolism disease, porphyrin metabolism disease, purine metabolism disease, amino acid metabolism disease, pyrimidine metabolism disease, disorder of acid-base balance, disorder of glutamate decarboxylase, tumor lysis syndrome, collagenous sprue, steroid metabolism disease, disorder of organic acid metabolism, skeletal fluorosis

Subtypes (4): familial hypercholesterolemia, familial lipoprotein lipase deficiency, hypercholesterolemia, familial, 4, hyperalphalipoproteinemia

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

3 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
381733	NM_001371904.1(APOA5):c.289C>T (p.Gln97Ter)	APOA5	Pathogenic	criteria provided, multiple submitters, no conflicts
917851	NM_000041.4(APOE):c.422A>G (p.Gln141Arg)	APOE	Uncertain significance	no assertion criteria provided
1330179	GRCh37/hg19 9q33.1-33.2(chr9:117853848-124633077)x1	PAPPA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOA5	Orphanet:530849	Familial apolipoprotein A5 deficiency
APOE	Orphanet:329481	Lipoprotein glomerulopathy
APOE	Orphanet:412	Dysbetalipoproteinemia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOA5	HGNC:17288	ENSG00000110243	Q6Q788	Apolipoprotein A-V	clinvar
APOE	HGNC:613	ENSG00000130203	P02649	Apolipoprotein E	clinvar
PAPPA	HGNC:8602	ENSG00000182752	Q13219	Pappalysin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APOA5	Apolipoprotein A-V	Minor apolipoprotein mainly associated with HDL and to a lesser extent with VLDL.
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.
PAPPA	Pappalysin-1	Metalloproteinase which specifically cleaves IGFBP-4 and IGFBP-5, resulting in release of bound IGF.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOA5	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
APOE	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
PAPPA	Protease	yes	3.4.24.79	Sushi_SCR_CCP_dom, Notch_dom, LamG-like

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right lobe of liver	1
skeletal muscle tissue of rectus abdominis	1
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
buccal mucosa cell	1
decidua	1
placenta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APOA5	45	tissue_specific	yes	right lobe of liver, liver, skeletal muscle tissue of rectus abdominis
APOE	267	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, right adrenal gland cortex
PAPPA	244	broad	marker	decidua, placenta, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOE	6,793
APOA5	1,919
PAPPA	942

Intra-cohort edges

A	B	Sources
APOA5	APOE	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOE	P02649	29
PAPPA	Q13219	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
APOA5	Q6Q788	72.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chylomicron remodeling	2	761.3×	4e-05	APOA5, APOE
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	3	86.5×	4e-05	APOA5, APOE, PAPPA
Plasma lipoprotein remodeling	2	317.2×	2e-04	APOA5, APOE
Plasma lipoprotein assembly, remodeling, and clearance	2	152.3×	5e-04	APOA5, APOE
Post-translational protein phosphorylation	2	66.8×	0.002	APOA5, APOE
Chylomicron clearance	1	761.3×	0.008	APOE
Chylomicron assembly	1	380.7×	0.012	APOE
HDL remodeling	1	380.7×	0.012	APOE
Plasma lipoprotein assembly	1	237.9×	0.015	APOE
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	211.5×	0.015	APOE
Scavenging by Class A Receptors	1	200.3×	0.015	APOE
Assembly of active LPL and LIPC lipase complexes	1	200.3×	0.015	APOA5
Transport of small molecules	2	16.8×	0.015	APOA5, APOE
Binding and Uptake of Ligands by Scavenger Receptors	1	181.3×	0.015	APOE
Plasma lipoprotein clearance	1	158.6×	0.016	APOE
NR1H2 and NR1H3-mediated signaling	1	131.3×	0.017	APOE
Metabolism of fat-soluble vitamins	1	126.9×	0.017	APOE
Post-translational protein modification	2	12.8×	0.017	APOA5, APOE
Nuclear signaling by ERBB4	1	115.3×	0.017	APOE
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	102.9×	0.018	APOE
Signaling by ERBB4	1	90.6×	0.020	APOE
Visual phototransduction	1	86.5×	0.020	APOE
Retinoid metabolism and transport	1	82.8×	0.020	APOE
Metabolism of proteins	2	8.2×	0.029	APOA5, APOE
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.031	APOA5
Metabolism	2	7.7×	0.031	APOA5, APOE
Metabolism of vitamins and cofactors	1	38.8×	0.036	APOE
Amyloid fiber formation	1	34.3×	0.038	APOE
Signaling by Nuclear Receptors	1	34.0×	0.038	APOE
Sensory Perception	1	31.7×	0.039	APOE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
very-low-density lipoprotein particle clearance	2	2246.9×	1e-05	APOA5, APOE
acylglycerol homeostasis	2	2246.9×	1e-05	APOA5, APOE
phospholipid efflux	2	749.0×	8e-05	APOA5, APOE
cholesterol efflux	2	351.1×	3e-04	APOA5, APOE
triglyceride homeostasis	2	321.0×	3e-04	APOA5, APOE
triglyceride metabolic process	2	295.6×	3e-04	APOA5, APOE
cholesterol metabolic process	2	130.6×	0.001	APOA5, APOE
lipid transport involved in lipid storage	1	5617.3×	0.002	APOE
maintenance of location in cell	1	5617.3×	0.002	APOE
intermediate-density lipoprotein particle clearance	1	5617.3×	0.002	APOE
positive regulation of lipid transport across blood-brain barrier	1	5617.3×	0.002	APOE
regulation of cellular response to very-low-density lipoprotein particle stimulus	1	5617.3×	0.002	APOE
cholesterol homeostasis	2	104.0×	0.002	APOA5, APOE
positive regulation of very-low-density lipoprotein particle remodeling	1	2808.7×	0.002	APOA5
triglyceride-rich lipoprotein particle clearance	1	2808.7×	0.002	APOE
regulation of amyloid-beta clearance	1	2808.7×	0.002	APOE
regulation of amyloid fibril formation	1	2808.7×	0.002	APOE
positive regulation of low-density lipoprotein particle receptor catabolic process	1	1872.4×	0.003	APOE
triglyceride-rich lipoprotein particle remodeling	1	1872.4×	0.003	APOA5
negative regulation of triglyceride metabolic process	1	1404.3×	0.003	APOE
positive regulation of phospholipid efflux	1	1404.3×	0.003	APOE
regulation of behavioral fear response	1	1404.3×	0.003	APOE
cellular response to lipoprotein particle stimulus	1	1123.5×	0.003	APOE
AMPA glutamate receptor clustering	1	1123.5×	0.003	APOE
NMDA glutamate receptor clustering	1	1123.5×	0.003	APOE
positive regulation of lipoprotein transport	1	1123.5×	0.003	APOE
positive regulation of dendritic spine maintenance	1	1123.5×	0.003	APOE
regulation of amyloid precursor protein catabolic process	1	1123.5×	0.003	APOE
positive regulation of amyloid fibril formation	1	1123.5×	0.003	APOE
chylomicron remnant clearance	1	936.2×	0.004	APOE

Therapeutics

Drugs indicated for this disease

0 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Coenzyme_A	Phase 3 (in late-stage trials)
Fenofibrate	Phase 3 (in late-stage trials)
Pantethine	Phase 3 (in late-stage trials)
Pelacarsen	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APOA5	0	0
APOE	0	0
PAPPA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAPPA	3.4.24.79	pappalysin-1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PAPPA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	APOA5, APOE

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APOA5	0	—
APOE	0	—
PAPPA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	11
Not specified	7
PHASE2	5
PHASE4	2
PHASE1/PHASE2	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00473655	PHASE4	COMPLETED	Effect of Rosuvastatin on Triglyceride Levels in Mexican Hypertriglyceridemic Patients
NCT01239992	PHASE4	TERMINATED	Effect of Niacin/Laropiprant on Postprandial Lipoprotein Metabolism in Patients With Dyslipoproteinemia
NCT05900141	PHASE3	ACTIVE_NOT_RECRUITING	An Open Label Extension (OLE) Study to Evaluate Long-term Safety and Tolerability of Pelacarsen (TQJ230)
NCT00000538	PHASE3	COMPLETED	Dietary Effects on Lipoproteins and Thrombogenic Activity
NCT00134498	PHASE3	COMPLETED	A Study Comparing The Efficacy & Safety Of Torcetrapib/Atorvastatin And Atorvastatin In Subjects With High Triglycerides
NCT00607373	PHASE3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	PHASE3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT01057654	PHASE3	COMPLETED	A Study Comparing the Mechanisms of Action of Lifibrol and Pravastatin
NCT01811082	PHASE3	COMPLETED	Comparison of Coenzyme A and Pantethine Capsule for Safety and Efficacy On Patients With Hyperlipidemia
NCT01878227	PHASE3	COMPLETED	Comparison of Coenzyme A and Fenofibrate for Safety and Efficacy On Patients With Hyperlipidemia
NCT01928342	PHASE2/PHASE3	UNKNOWN	The Effects of Coenzyme A Combined With Statin on Serum Lipids in Patients With Hyperlipidemia
NCT02658175	PHASE3	COMPLETED	The Approach Open Label Study: A Study of Volanesorsen (Formerly IONIS-APOCIIIRx) in Participants With Familial Chylomicronemia Syndrome
NCT05305664	PHASE3	COMPLETED	A Multicenter Trial Assessing the Impact of Lipoprotein(a) Lowering With Pelacarsen (TQJ230) on the Rate of Weekly Lipoprotein Apheresis Sessions in Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease in Germany
NCT05425745	PHASE3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT07172646	PHASE1/PHASE2	RECRUITING	A Study of SRSD216 in Patients With Elevated Lipoprotein (a)
NCT00477594	PHASE2	COMPLETED	Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia
NCT01146522	PHASE1/PHASE2	COMPLETED	Safety, Tolerability,Pharmacokinetics(PK)and Pharmacodynamics(PD)Assessment of LCQ908 in Patients With Severe Hypertriglyceridemia
NCT01645046	PHASE2	COMPLETED	The Effects of Coenzyme A on Serum Lipids in Patients With Hyperlipidemia
NCT03360747	PHASE2	COMPLETED	Phase 2 Study of AKCEA-ANGPTL3-LRx (ISIS 703802) in Participants With Familial Chylomicronemia Syndrome (FCS)
NCT04516291	PHASE2	COMPLETED	A Dose-Ranging Study With Vupanorsen (TRANSLATE-TIMI 70)
NCT05256654	PHASE2	COMPLETED	A Study of LY3561774 in Participants With Mixed Dyslipidemia
NCT07405814	Not specified	RECRUITING	Clinical Trial On The Effect Of Artisterol On Risk Factors In Individuals With Suboptimal Cholesterol Levels
NCT00001226	Not specified	COMPLETED	Lipoprotein Metabolism in Normal Volunteers and Patients With Abnormal Levels of Lipoproteins
NCT00005128	Not specified	COMPLETED	Lipid Research Clinics Population Studies
NCT00005368	Not specified	COMPLETED	Genetic Epidemiology of Hypertriglyceridemia
NCT01064934	Not specified	WITHDRAWN	Randomized Controlled Trial of Lipid Apheresis in Patients With Elevated Lipoprotein(a)
NCT02933138	Not specified	COMPLETED	Plasma Triglyceride Lipolysis in Multifactorial Chylomicronemia
NCT06163443	Not specified	COMPLETED	Evaluating the Impact of B Vitamin Supplementation (Soloways™) on Homocysteine and LDL-C Levels in Patients With MTHFR, MTR, and MTRR Polymorphisms.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MIPOMERSEN	4	4
ROSUVASTATIN	4	2
FENOFIBRATE	4	1
LAROPIPRANT	4	1
NIACIN	4	1
PRAVASTATIN	4	1
THIAMINE	4	1
VOLANESORSEN	4	1
COENZYME_A	3	4
LIFIBROL	3	1
OBICETRAPIB	3	1
PANTETHINE	3	1
PELACARSEN	3	1
TORCETRAPIB	3	1
VUPANORSEN	2	2
SOLBINSIRAN	2	1
CHEMBL4756598	0	4
CHEMBL1357356	0	1
CHEMBL3184321	0	1