APOA4

Summary

APOA4 (apolipoprotein A4, HGNC:602) is a protein-coding gene on chromosome 11q23.3, encoding Apolipoprotein A-IV (P06727). May have a role in chylomicrons and VLDL secretion and catabolism.

Apoliprotein (apo) A-IV gene contains 3 exons separated by two introns. A sequence polymorphism has been identified in the 3’UTR of the third exon. The primary translation product is a 396-residue preprotein which after proteolytic processing is secreted its primary site of synthesis, the intestine, in association with chylomicron particles. Although its precise function is not known, apo A-IV is a potent activator of lecithin-cholesterol acyltransferase in vitro.

Source: NCBI Gene 337 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary amyloidosis (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 48
• Clinical variants (ClinVar): 188 total — 2 pathogenic
• Phenotypes (HPO): 17
• MANE Select transcript: NM_000482

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:602
Approved symbol	APOA4
Name	apolipoprotein A4
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000110244
Ensembl biotype	protein_coding
OMIM	107690
Entrez	337

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000357780

RefSeq mRNA: 1 — MANE Select: NM_000482 NM_000482

CCDS: CCDS31681

Canonical transcript exons

ENST00000357780 — 3 exons

Exon	Start	End
ENSE00000795778	116820700	116821881
ENSE00001620503	116823143	116823304
ENSE00001717760	116822659	116822785

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 99.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 22.4678 / max 12555.6031, expressed in 146 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122436	22.2904	143
122434	0.0498	15
122438	0.0208	7
122430	0.0205	7
122432	0.0173	8
122431	0.0138	6
122433	0.0138	6
122429	0.0132	7
122435	0.0110	6
122437	0.0094	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.97	gold quality
ileal mucosa	UBERON:0000331	99.48	gold quality
duodenum	UBERON:0002114	98.35	gold quality
small intestine	UBERON:0002108	91.42	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.47	gold quality
jejunum	UBERON:0002115	89.62	gold quality
right lobe of liver	UBERON:0001114	89.56	gold quality
type B pancreatic cell	CL:0000169	88.19	silver quality
olfactory bulb	UBERON:0002264	86.31	gold quality
buccal mucosa cell	CL:0002336	84.31	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	82.84	gold quality
liver	UBERON:0002107	82.20	gold quality
tendon of biceps brachii	UBERON:0008188	81.97	silver quality
gluteal muscle	UBERON:0002000	79.48	gold quality
vastus lateralis	UBERON:0001379	79.33	gold quality
vena cava	UBERON:0004087	79.01	silver quality
diaphragm	UBERON:0001103	78.90	gold quality
endometrium epithelium	UBERON:0004811	78.86	gold quality
upper arm skin	UBERON:0004263	76.69	gold quality
cervix squamous epithelium	UBERON:0006922	75.47	gold quality
medial globus pallidus	UBERON:0002477	75.03	silver quality
male germ cell	CL:0000015	74.89	gold quality
oocyte	CL:0000023	74.83	gold quality
pericardium	UBERON:0002407	74.54	silver quality
frontal pole	UBERON:0002795	74.53	gold quality
paraflocculus	UBERON:0005351	74.32	gold quality
middle frontal gyrus	UBERON:0002702	73.73	gold quality
pons	UBERON:0000988	73.58	silver quality
sperm	CL:0000019	73.55	gold quality
cervix epithelium	UBERON:0004801	73.08	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	12758.33
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB3, ESRRA, HNF4A, HNF4G, NR2F1, PPARA, PPARG, RORA, RXRA, STAT3

miRNA regulators (miRDB)

11 targeting APOA4, 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-6721-5P	99.93	68.92	2981
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-3934-5P	99.67	64.04	846
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-552-3P	96.68	64.12	1026

Literature-anchored findings (GeneRIF, showing 40)

• Effect of human Apo AIV against lipid peroxidation of very low density lipoproteins (PMID:11841825)
• Interfacial exclusion pressure determines the ability of apolipoprotein A-IV truncation mutants to activate cholesterol ester transfer protein (PMID:11940599)
• Association of apolipoprotein A-IV genotype with blood glucose, plasma lipoprotein levels, total cholesterol, and triglycerides in a gender-specific manner (PMID:12121350)
• Association between APOA4 and triglycerides (TG) reflects linkage disequilibrium with known TG-raising sites. (PMID:12417525)
• Apolipoprotein AIV gene variant S347 is associated with increased risk of coronary heart disease and lower plasma apolipoprotein AIV levels. (PMID:12676816)
• No major differences exist in the apoA-IV plasma distribution pattern between coronary artery disease patients and controls; therefore, the antiatherogenic effect of apoA-IV has to be explained by other functional properties of apoA-IV (PMID:12777472)
• H-apoA-IV expression in apoE(0) mice reduces atherogenesis & decreases proinflammatory cytokine secretion after LPS administration. h-apoA-IV exerts its protective role by specifically, but partially, inhibiting LPS-induced stimulation of monocytes. (PMID:14751811)
• Results provide the first direct support for the hypothesis that apolipoprotein A-IV is an endogenous anti-inflammatory protein. (PMID:15254593)
• apoA-IV may physically interact with apoB in the secretory pathway and affects intracellular distribution of apoB (PMID:15258202)
• Human apoA-I/C-III/A-IV transgenic rabbits may provide a reliable model for studies of the transcriptional regulation of the cluster, and for evaluating the effects of different agents on the expression of the three genes. (PMID:15304365)
• the amphipathic alpha helices in apoA4 form a large domain that may be similar to the N-terminal helical bundle domains of apoA1 and apoE but apoA4 lacks the C-terminal lipid-binding and cholesterol efflux-promoting domain of these apolipoproteins (PMID:15311933)
• the apoCIII enhancer regulates expression of apoAI, apo-CIII, and apoAIV but not apoAV in vivo; the entire cluster has roles in regulating lipid metabolism (PMID:15649902)
• the apo A-IV-2 allele is associated with a modest reduction in plasma triglyceride levels in the general population (PMID:15721024)
• A significant association between the presence of apolipoprotein A-IV His allele and cerebrovascular disease, obesity and depression. (PMID:15806598)
• HNF-4alpha and gamma functionally interact with a second hormone-responsive element present in the proximal region of the human apoA-IV promoter. (PMID:15928313)
• ApoA-IV immunostaining was detected in proximal and distal tubular cells, capillaries and blood vessels but not inside glomeruli (PMID:16105043)
• novel role for Apo A-IV in the regulation of intracellular glutathione redox balance and the modulation of redox-dependent apoptosis via stimulation of G6PD activity (PMID:16120654)
• the C-terminal sequence can modulate the conformation and lipid affinity of apoA-IV (PMID:16159879)
• While female carriers of the APOA4(347) S allele had lower TG concentrations than those with the common T/T allele, males with the S allele had higher concentrations. (PMID:16326171)
• E-cadherin controls enterocyte-specific expression of genes, such as the apoA-IV gene, through the control of hepatic nuclear factor 4alpha nuclear abundance (PMID:16338932)
• Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans (PMID:16602826)
• Potential interactions between APOA4 genotypes and metabolic/oxidative stress components of the diabetic milieu leading to rapid progression of atherosclerosis. (PMID:16770585)
• the variability in APOA1/C3/A4/A5 gene cluster may affect TG and HDL levels in women with type 2 diabetes (PMID:16781717)
• Data demonstrate that the increase of apoA-IV caused by renal impairment is significantly modulated by low levels of serum albumin as a measure for the severity of the nephrotic syndrome. (PMID:16788210)
• the induction of apoA-IV expression in fasting and diabetes likely involves PGC-1 alpha-mediated coactivation of HNF-4 alpha in addition to glucocorticoid-dependent actions (PMID:16929032)
• apoA-IV can bind to LDL & acts as a site-specific antioxidant. reduced inhibition of LDL oxidation by apoA-IV-S347 compared to wild type apoA-IV may account for previous association of the APOA4 S347 variant with increased CHD risk & oxidative stress. (PMID:16945374)
• ApoA-IV polymorphism is not associated with either disease activity or apoA-IV plasma levels in patients with Crohn’s disease or ulcerative colitis. (PMID:17206692)
• Variants may play an important role in the individual sensitivity of lipid parameters to dietary composition in men. (PMID:17378725)
• Polymorphisms in ApoAI-CIII-AIV gene cluster are associated with risks of diabetes and coronary heart disease. (PMID:17654446)
• ApoA-IV expression is significantly impaired in inflammatory bowel diseases mucosa, even in non-inflamed regions. (PMID:17712726)
• genetic variation of 3’ flanking region of ApoA-I (PstI), 3’ untranslated region of ApoC-III (SstI) and intron 2 of ApoA-IV (XbaI) in 193 angiographically diagnosed coronary heart disease Punjab patients (PMID:17825930)
• lipid-free apoA-IV exists as a complex helical bundle with the N and C termini in close proximity (PMID:18430727)
• Codon 9, Msp I and VNTR polymorphisms in the apo A-IV gene are associated with type-IV hyperlipoproteinaemia in a Chinese population. (PMID:18664021)
• the apoCIII enhancer contributes to the maintenance of an active chromatin subdomain of the apoAI/CIII/AIV genes, but not apoAV (PMID:18678879)
• Blood levels increase after gastric bypass in morbid obesity, which may contribute to weight loss as well as the improvements in inflammation and cardiovascular disease. (PMID:18948973)
• Reduced apolipoprotein A-IV expression is associated with ovarian cancer. (PMID:19336561)
• results indicate that human apoA-IV is regulated directly by PPARalphavia the -2979/-2967 PPRE (PMID:19433068)
• We have identified new associations between SNPs in the APOA1/C3/A4/A5 gene cluster and altered postprandial lipid metabolism. (PMID:19592705)
• polymorphisms in the apolipoprotein A1/C3/A4/A5 gene cluster may have roles in familial combined hyperlipidaemia in Hong Kong Chinese (PMID:19732897)
• The two common aminoacid substitutions,T347S and Q360H , have no effect on the ability of apoA-IV to maintain endothelial homeostasis. (PMID:20117098)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Apoa4	ENSMUSG00000032080
rattus_norvegicus	Apoa4	ENSRNOG00000055909

Paralogs (3): APOA5 (ENSG00000110243), APOA1 (ENSG00000118137), APOE (ENSG00000130203)

Protein

Protein identifiers

Apolipoprotein A-IV — P06727 (reviewed: P06727)

Alternative names: Apolipoprotein A4

All UniProt accessions (1): P06727

UniProt curated annotations — full annotation on UniProt →

Function. May have a role in chylomicrons and VLDL secretion and catabolism. Required for efficient activation of lipoprotein lipase by ApoC-II; potent activator of LCAT. Apoa-IV is a major component of HDL and chylomicrons.

Subunit / interactions. Homodimer.

Subcellular location. Secreted.

Tissue specificity. Synthesized primarily in the intestine and secreted in plasma.

Post-translational modifications. Phosphorylation sites are present in the extracellular medium.

Disease relevance. Tubulointerstitial kidney disease, autosomal dominant 6 (ADTKD6) [MIM:621106] A form of autosomal dominant tubulointerstitial kidney disease, a genetically heterogeneous disorder characterized by slowly progressive loss of kidney function, bland urinary sediment, hyperuricemia, absent or mildly increased albuminuria, lack of severe hypertension during the early stages, and normal or small kidneys on ultrasound. Renal histology shows variable abnormalities including interstitial fibrosis with tubular atrophy, microcystic dilatation of the tubules, thickening of tubular basement membranes, medullary cysts, and secondary glomerulosclerotic or glomerulocystic changes with abnormal glomerular tufting. There is significant variability, as well as incomplete penetrance. ADTKD6 is characterized by the onset of slowly progressive renal failure in mid-to-late adulthood, and the presence of APOA4-positive amyloid deposits in the renal medulla without systemic amyloid deposition in other organs. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Nine of the thirteen 22-amino acid tandem repeats (each 22-mer is actually a tandem array of two, A and B, related 11-mers) occurring in this sequence are predicted to be highly alpha-helical, and many of these helices are amphipathic. They may therefore serve as lipid-binding domains with lecithin:cholesterol acyltransferase (LCAT) activating abilities.

Polymorphism. Eight alleles have been characterized (APOA-IV0 to APOA-IV7). APOA-IV1 is the major allele (90%), APOA-IV2 is also common (8%), the others are rare alleles.

Similarity. Belongs to the apolipoprotein A1/A4/E family.

RefSeq proteins (1): NP_000473* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000074	ApoA_E	Family
IPR050163	Apolipoprotein_A1/A4/E	Family

Pfam: PF01442

UniProt features (47 total): sequence variant 19, repeat 13, helix 7, region of interest 2, sequence conflict 2, signal peptide 1, chain 1, compositionally biased region 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3S84	X-RAY DIFFRACTION	2.4
9HX4	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P06727-F1	81.14	0.43

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-8963888	Chylomicron assembly
R-HSA-8963889	Assembly of active LPL and LIPC lipase complexes
R-HSA-8963901	Chylomicron remodeling
R-HSA-975634	Retinoid metabolism and transport
R-HSA-977225	Amyloid fiber formation
R-HSA-1430728	Metabolism
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-2187338	Visual phototransduction
R-HSA-382551	Transport of small molecules
R-HSA-392499	Metabolism of proteins
R-HSA-6806667	Metabolism of fat-soluble vitamins
R-HSA-8963898	Plasma lipoprotein assembly
R-HSA-8963899	Plasma lipoprotein remodeling
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 272 (showing top): GOBP_ACYLGLYCEROL_HOMEOSTASIS, GOBP_DIGESTION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLCHOLINE_METABOLIC_PROCESS, GOBP_REGULATION_OF_TRIGLYCERIDE_METABOLIC_PROCESS, GOBP_STEROL_HOMEOSTASIS, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOBP_HYDROGEN_PEROXIDE_CATABOLIC_PROCESS, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOCC_CELL_SURFACE, GOBP_SUPEROXIDE_METABOLIC_PROCESS, GOBP_REGENERATION, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_RESPONSE_TO_AXON_INJURY

GO Biological Process (30): innate immune response in mucosa (GO:0002227), lipid transport (GO:0006869), response to lipid hydroperoxide (GO:0006982), leukocyte cell-cell adhesion (GO:0007159), cholesterol metabolic process (GO:0008203), positive regulation of triglyceride catabolic process (GO:0010898), peripheral nervous system axon regeneration (GO:0014012), lipid catabolic process (GO:0016042), removal of superoxide radicals (GO:0019430), regulation of intestinal cholesterol absorption (GO:0030300), regulation of cholesterol transport (GO:0032374), cholesterol efflux (GO:0033344), phospholipid efflux (GO:0033700), response to triglyceride (GO:0034014), chylomicron remodeling (GO:0034371), very-low-density lipoprotein particle remodeling (GO:0034372), high-density lipoprotein particle remodeling (GO:0034375), chylomicron assembly (GO:0034378), negative regulation of plasma lipoprotein oxidation (GO:0034445), response to stilbenoid (GO:0035634), lipoprotein metabolic process (GO:0042157), cholesterol homeostasis (GO:0042632), hydrogen peroxide catabolic process (GO:0042744), reverse cholesterol transport (GO:0043691), positive regulation of fatty acid biosynthetic process (GO:0045723), phosphatidylcholine metabolic process (GO:0046470), lipid homeostasis (GO:0055088), acylglycerol homeostasis (GO:0055090), protein-lipid complex assembly (GO:0065005), response to stress (GO:0006950)

GO Molecular Function (11): lipid carrier activity (GO:0005319), copper ion binding (GO:0005507), phospholipid binding (GO:0005543), lipid binding (GO:0008289), antioxidant activity (GO:0016209), phosphatidylcholine binding (GO:0031210), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), phosphatidylcholine-sterol O-acyltransferase activator activity (GO:0060228), cholesterol transfer activity (GO:0120020), protein binding (GO:0005515)

GO Cellular Component (14): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), early endosome (GO:0005769), endoplasmic reticulum lumen (GO:0005788), cytosol (GO:0005829), very-low-density lipoprotein particle (GO:0034361), low-density lipoprotein particle (GO:0034362), high-density lipoprotein particle (GO:0034364), chylomicron (GO:0042627), synapse (GO:0045202), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), extracellular vesicle (GO:1903561), cell surface (GO:0009986)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Plasma lipoprotein remodeling	2
Plasma lipoprotein assembly, remodeling, and clearance	2
Plasma lipoprotein assembly	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Metabolism of proteins	1
Transport of small molecules	1
Metabolism	1
Sensory Perception	1
Metabolism of vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
plasma lipoprotein particle	3
response to lipid	2
cellular oxidant detoxification	2
cholesterol transport	2
triglyceride-rich lipoprotein particle remodeling	2
binding	2
extracellular region	2
mucosal immune response	1
innate immune response	1
transport	1
lipid localization	1
response to hydroperoxide	1
cell-cell adhesion	1
sterol metabolic process	1
secondary alcohol metabolic process	1
regulation of triglyceride catabolic process	1
triglyceride catabolic process	1
positive regulation of lipid catabolic process	1
positive regulation of triglyceride metabolic process	1
axon regeneration	1
lipid metabolic process	1
catabolic process	1
superoxide metabolic process	1
cellular response to superoxide	1
intestinal cholesterol absorption	1
regulation of intestinal lipid absorption	1
regulation of sterol transport	1
phospholipid transport	1
response to oxygen-containing compound	1
plasma lipoprotein particle remodeling	1
plasma lipoprotein particle assembly	1
plasma lipoprotein particle oxidation	1
regulation of plasma lipoprotein oxidation	1
negative regulation of cellular component organization	1
negative regulation of multicellular organismal process	1
response to chemical	1
molecular carrier activity	1
transition metal ion binding	1
lipid binding	1

Protein interactions and networks

STRING

1212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APOA4	APOC3	P02656	982
APOA4	APOE	P02649	979
APOA4	APOA2	P02652	967
APOA4	APOB	P04114	964
APOA4	APOC2	P02655	934
APOA4	CLU	P10909	918
APOA4	APOC1	P02654	891
APOA4	APOA1	P02647	890
APOA4	APOD	P05090	864
APOA4	APOM	O95445	824
APOA4	ALB	P02768	807
APOA4	APOF	Q13790	802
APOA4	CETP	P11597	787
APOA4	FGG	P02679	768
APOA4	SERPINA1	P01009	767

IntAct

56 interactions, top by confidence:

A	B	Type	Score
APOA4	APOA4	psi-mi:“MI:0407”(direct interaction)	0.680
APOA4	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
APOA4	CMTM5	psi-mi:“MI:0915”(physical association)	0.560
APOA4	MAGEA6	psi-mi:“MI:0915”(physical association)	0.560
APOA4	CMTM4	psi-mi:“MI:0915”(physical association)	0.560
CASP6	APOA4	psi-mi:“MI:0915”(physical association)	0.560
SH3GLB1	APOA4	psi-mi:“MI:0915”(physical association)	0.560
NR1D1	APOA4	psi-mi:“MI:0403”(colocalization)	0.520
NR1D1	APOA4	psi-mi:“MI:2364”(proximity)	0.520
NR1D1	APOA4	psi-mi:“MI:0915”(physical association)	0.520
	LECT2	psi-mi:“MI:0915”(physical association)	0.400
	CD5L	psi-mi:“MI:0915”(physical association)	0.400
ALB	CNOT1	psi-mi:“MI:0914”(association)	0.350
ALB	F2	psi-mi:“MI:0914”(association)	0.350
ALB	SH3BP5	psi-mi:“MI:0914”(association)	0.350
APP	APOA1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350

ESM2 similar proteins: A0A1S3EL69, A0A2K5EJU6, A0A2K6TRM6, A0A2U3YVN9, A0A2Y9HKB5, D7PGV9, F7FQM7, F7HUS6, G5BQH5, H0VVW3, I3M072, M3W955, O18759, O42296, O46409, O57523, P02651, P04639, P06727, P06728, P08250, P09809, P0DMA6, P0DMA8, P0DMA9, P0DMB0, P0DMC0, P0DMS2, P0DMS3, P0DMS5, P0DP49, P0DSO8, P0DTS0, P0DTS1, P0DTU5, P0DTU6, P0DTU7, P0DTU9, P0DTV0, P0DTV1

Diamond homologs: A0A2U3YVN9, A0A2Y9HKB5, E2RE76, M3W955, O46409, P02651, P06727, P06728, P08226, P0DSO8, P0DTS0, P0DTS1, P33621, Q28758, Q32PJ2, O42364, P02650, P0DUY2, P0DUY9, P0DUZ3, P0DUZ5, P0DUZ8, P0DUY3, P0DUY7, A0A0D9S1R0, A0A2Y9GHM3, A0A6P3R0Z0, A0A6P6DKR7, G5CBM7, L5KM50, P02649, P05770, P0DKU9, P0DKW5, P0DKW6, P0DKW7, P0DKW8, P0DKY2, P0DML7, P0DML8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TFEB	“up-regulates quantity by expression”	APOA4	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	5	25.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	116
Likely benign	38
Benign	27

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3764740	NM_000482.4(APOA4):c.196C>G (p.Leu66Val)	Pathogenic
3764741	NM_000482.4(APOA4):c.97G>A (p.Asp33Asn)	Pathogenic

SpliceAI

133 predictions. Top by Δscore:

Variant	Effect	Δscore
11:116821877:GGGCA:G	acceptor_gain	1.0000
11:116821878:GGCA:G	acceptor_gain	1.0000
11:116821879:GCA:G	acceptor_gain	1.0000
11:116821880:CA:C	acceptor_gain	1.0000
11:116821880:CAC:C	acceptor_gain	1.0000
11:116821882:C:CC	acceptor_gain	1.0000
11:116821884:G:C	acceptor_gain	1.0000
11:116822657:A:AC	donor_gain	1.0000
11:116822658:C:CC	donor_gain	1.0000
11:116823138:CTCA:C	donor_loss	1.0000
11:116823139:TCA:T	donor_loss	1.0000
11:116823140:CACCG:C	donor_loss	1.0000
11:116822647:AGTC:A	donor_gain	0.9900
11:116822654:CTTA:C	donor_loss	0.9900
11:116822655:TTAC:T	donor_loss	0.9900
11:116822657:ACT:A	donor_loss	0.9900
11:116822658:C:CG	donor_loss	0.9900
11:116822783:CTC:C	acceptor_gain	0.9900
11:116823135:CTACT:C	donor_loss	0.9900
11:116823137:ACT:A	donor_loss	0.9900
11:116823141:A:AC	donor_gain	0.9900
11:116823142:C:CC	donor_gain	0.9900
11:116823142:CCGG:C	donor_gain	0.9900
11:116821878:GGCAC:G	acceptor_gain	0.9800
11:116821879:GCAC:G	acceptor_gain	0.9800
11:116821880:CACT:C	acceptor_gain	0.9800
11:116821881:AC:A	acceptor_gain	0.9800
11:116821882:C:CA	acceptor_gain	0.9800
11:116821883:T:G	acceptor_gain	0.9800
11:116822650:C:A	donor_gain	0.9800

AlphaMissense

2596 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:116821402:A:G	L219P	0.979
11:116822711:C:G	A42P	0.970
11:116821018:A:G	L347P	0.968
11:116821808:C:G	A84P	0.966
11:116821600:A:G	L153P	0.962
11:116822702:C:G	A45P	0.960
11:116821303:A:G	L252P	0.958
11:116822662:A:G	L58P	0.957
11:116821149:G:C	F303L	0.953
11:116821149:G:T	F303L	0.953
11:116821151:A:G	F303L	0.953
11:116821313:C:G	A249P	0.953
11:116821336:A:G	L241P	0.953
11:116822722:A:G	L38P	0.953
11:116821831:A:G	L76P	0.951
11:116822739:C:A	W32C	0.951
11:116822739:C:G	W32C	0.951
11:116821807:G:T	A84D	0.948
11:116821732:A:G	L109P	0.947
11:116821468:A:G	L197P	0.945
11:116822710:G:T	A42D	0.945
11:116821270:A:G	L263P	0.941
11:116821720:A:G	L113P	0.940
11:116821588:A:G	L157P	0.934
11:116821633:A:G	L142P	0.934
11:116821819:A:G	L80P	0.932
11:116821666:A:G	L131P	0.929
11:116821084:A:G	L325P	0.927
11:116821357:A:G	L234P	0.927
11:116823160:G:T	A11D	0.927

dbSNP variants (sampled 300 via entrez): RS1001077796 (11:116822420 A>T), RS1001224610 (11:116823110 C>T), RS1003472312 (11:116823296 G>A,T), RS1003594865 (11:116823868 G>T), RS1003970272 (11:116824181 T>G), RS1004953891 (11:116821770 C>A,T), RS1005552974 (11:116824505 C>G,T), RS1006964182 (11:116821469 G>A), RS1007036347 (11:116821281 A>C,G), RS1007298106 (11:116820486 G>T), RS1007412635 (11:116823790 G>A), RS1007445104 (11:116823611 C>G,T), RS1007515419 (11:116823455 C>T), RS1007516753 (11:116825178 G>C), RS1009484546 (11:116823135 CT>C)

Disease associations

OMIM: gene MIM:107690 | disease phenotypes: MIM:621106

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary amyloidosis	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal dominant medullary cystic kidney disease with or without hyperuricemia	Limited	AD

Mondo (2): tubulointerstitial kidney disease, autosomal dominant 6 (MONDO:0976234), hereditary amyloidosis (MONDO:0018634)

Orphanet (0):

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000092	Renal tubular atrophy
HP:0000093	Proteinuria
HP:0000096	Glomerular sclerosis
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0001997	Gout
HP:0003124	Hypercholesterolemia
HP:0003596	Middle age onset
HP:0003774	Stage 5 chronic kidney disease
HP:0012213	Decreased glomerular filtration rate
HP:0012622	Chronic kidney disease
HP:0031264	Abnormal Bowman capsule morphology
HP:0032945	Renal interstitial inflammation
HP:0032948	Renal interstitial fibrosis
HP:0033289	Glomerular basement membrane wrinkling
HP:0033499	Glomerular basement membrane electron dense deposits

GWAS associations

48 associations (top):

Study	Trait	p-value
GCST000138_5	Triglycerides	2.000000e-17
GCST000139_1	Triglycerides	1.000000e-26
GCST000282_1	LDL cholesterol	5.000000e-13
GCST000285_3	Cholesterol, total	7.000000e-07
GCST000286_6	Triglycerides	4.000000e-62
GCST000289_6	Triglycerides	5.000000e-13
GCST000290_3	HDL cholesterol	1.000000e-12
GCST000300_1	Triglycerides	3.000000e-29
GCST000583_1	Hematological and biochemical traits	9.000000e-10
GCST000584_2	Triglycerides	1.000000e-49
GCST000755_1	HDL cholesterol	5.000000e-47
GCST000758_19	Triglycerides	7.000000e-240
GCST000759_31	LDL cholesterol	1.000000e-26
GCST000760_51	Cholesterol, total	6.000000e-57
GCST000805_4	HDL cholesterol	2.000000e-11
GCST000807_7	LDL cholesterol	2.000000e-06
GCST000809_11	Triglycerides	4.000000e-21
GCST000998_20	Coronary heart disease	1.000000e-17
GCST001230_3	Triglycerides	2.000000e-86
GCST001392_8	Lipid metabolism phenotypes	8.000000e-20
GCST001639_26	Metabolite levels	8.000000e-20
GCST001905_3	Hypertriglyceridemia	5.000000e-35
GCST002321_16	Lipid traits	2.000000e-59
GCST003215_2	HDL cholesterol	2.000000e-85
GCST003217_6	Triglycerides	4.000000e-213
GCST003364_2	Triglyceride levels	1.000000e-30
GCST003590_1	Apolipoprotein A-IV levels	7.000000e-44
GCST004232_3	HDL cholesterol levels	3.000000e-71
GCST004232_40	HDL cholesterol levels	2.000000e-71
GCST004233_51	LDL cholesterol levels	3.000000e-18

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004529	lipid measurement
EFO:0004723	coronary artery calcification
EFO:0007848	apolipoprotein A-IV measurement
EFO:0000195	metabolic syndrome
EFO:0004340	body mass index

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D028226	Amyloidosis, Familial	C16.320.565.176; C18.452.648.176; C18.452.845.500.075

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs675	APOA4		0.00	0
rs5090	APOA4		0.00	0
rs5092	APOA4		0.00	0
rs5104	APOA4		0.00	0
rs1263177	APOA4		0.00	0
rs2854117	APOA4, APOC3	3	4.25	1	ritonavir

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, increases methylation	3
bisphenol A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, affects methylation	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
dicrotophos	decreases expression	1
methyleugenol	decreases expression	1
perfluorooctanoic acid	increases expression	1
stearic acid	increases expression	1
benazol P	affects expression	1
iron(II)-ascorbic acid complex	decreases expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Olanzapine	affects phosphorylation	1
Rosiglitazone	decreases expression	1
Rifaximin	increases response to substance, increases expression	1
Arsenic	affects methylation	1
Cadmium	affects binding	1
Chenodeoxycholic Acid	decreases expression	1
Copper	affects binding	1
Fructose	increases expression	1
Hydrogen Peroxide	affects expression	1
Cholesterol, HDL	affects abundance	1
N-Nitrosopyrrolidine	decreases expression	1
Nickel	affects binding	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D6BM	HyCyte Hep-G2 KO-hAPOA4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03862807	PHASE3	COMPLETED	Patisiran in Patients With Hereditary Transthyretin-mediated Amyloidosis (hATTR Amyloidosis) Disease Progression Post-Liver Transplant
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00294671	PHASE2/PHASE3	COMPLETED	The Effect of Diflunisal on Familial Amyloidosis
NCT04695340	Not specified	WITHDRAWN	Effect of Psyllium (Plantago Ovata) on Digestive Disorders in Familial Amyloidosis
NCT05489549	Not specified	RECRUITING	Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers
NCT05940922	Not specified	UNKNOWN	RWE-based Treatment Patterns and Outcomes in CIDP
NCT07213297	Not specified	RECRUITING	Comprehensive Program for Hereditary Transthyretin Amyloidosis