Hypertriglyceridemia

Summary

Hypertriglyceridemia (MONDO:0005347) is a disease caused by CREB3L3 (GenCC Strong), with 14 cohort genes (93 GWAS associations across 15 studies) and 232 clinical trials. The dominant Reactome pathway is Chylomicron remodeling (4 cohort genes). Top therapeutic interventions include omega-3-acid ethyl esters, fenofibrate, and fish oil.

At a glance

• Causal gene: CREB3L3 (GenCC Strong)
• Cohort genes: 14
• GWAS associations: 93
• ClinVar variants: 8
• Clinical trials: 232

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertriglyceridemia
Mondo ID	MONDO:0005347
EFO	EFO:0004211
MeSH	D015228
SNOMED CT	302870006
UMLS	C0813230
MedGen	167238
Is cancer (heuristic)	no

Also known as: hypertriglyceridemia · hypertriglyceridemia (disease)

Data availability: 8 ClinVar variants · 93 GWAS associations (15 studies) · 2 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 2 Mondo subtypes.

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

Related subtypes (36): glutaric aciduria, mineral metabolism disease, xanthinuria, chondrocalcinosis, ochronosis disorder, glucose metabolism disease, diabetic kidney disease, xanthoma, diabetic retinopathy, 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, hyperlipoproteinemia, 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 (2): hypertriglyceridemia 1, hypertriglyceridemia 2

Genetics & variants

GWAS landscape

93 GWAS associations across 15 studies. Top hits map to 19 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs651821	5e-228	APOA5	T	1.9
rs1260326	1e-41	GCKR	C	0.8
rs438811	7e-37	APOC1	T	1.4
rs662799	5e-34	APOA5	G	1.77
rs10503669	3e-28	LPL - RPL30P9	A	0.7
rs7350481	2e-24	LINC02702 - BUD13	?	10.19
rs1558861	4e-24	LINC02702 - BUD13	C	1.74
rs964184	5e-24	ZPR1	G	3.28
rs3825041	7e-20	BUD13; ZPR1; LINC02702 - BUD13	C	1.96
rs2954021	1e-19	TRIB1AL	G	1.2
rs909267	3e-16	VARS1	C	1.3
rs17145732	8e-15	BCL7B	G	0.8
rs6589566	1e-14	ZPR1	?	1.48
rs12037659	2e-14	DOCK7	T	0.8
rs17145738	2e-13	TBL2	C	1.82
rs780093	3e-12	GCKR	?	1.37
rs671	7e-12	ALDH2	A	0.8
rs72643559	8e-10	FADS2	C	1.1
rs6531981	9e-10	HSD17B11	A	1.1
rs58542926	2e-09	TM6SF2	T	0.8
rs8033573	9e-09	SNHG21, FSD2	A	0.9
rs780094	2e-08	GCKR	T	1.22
rs6982502	2e-08	TRIB1AL	C	1.35
rs738409	3e-08	PNPLA3	G	0.9
rs4635554	2e-07	TDRD15 - NUTF2P8	G	1.67
rs7016880	2e-07	LPL - RPL30P9	?	3.13
rs10911205	2e-07	LAMC1; LAMC2; LAMC1	?	1.33
rs1837842	2e-07	LPL - RPL30P9	?	1.35
rs17411126	2e-07	LPL - RPL30P9	?	1.35
rs7396835	2e-07	LNC-RHL1	?	1.27

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST009662	Oh SW	2020	7,423	7,423	Genome-wide association study of metabolic syndrome in Korean populations.
GCST90244626	Kim YS	2022	6,446	44,362	Lifestage Sex-Specific Genetic Effects on Metabolic Disorders in an Adult Population in Korea: The Korean Genome and Epidemiology Study.
GCST90244627	Kim YS	2022	3,757	15,838	Lifestage Sex-Specific Genetic Effects on Metabolic Disorders in an Adult Population in Korea: The Korean Genome and Epidemiology Study.
GCST90244628	Kim YS	2022	2,689	28,524	Lifestage Sex-Specific Genetic Effects on Metabolic Disorders in an Adult Population in Korea: The Korean Genome and Epidemiology Study.
GCST009657	Oh SW	2020	2,253	2,253	Genome-wide association study of metabolic syndrome in Korean populations.
GCST90244631	Kim YS	2022	1,595	5,584	Lifestage Sex-Specific Genetic Effects on Metabolic Disorders in an Adult Population in Korea: The Korean Genome and Epidemiology Study.
GCST90244633	Kim YS	2022	1,522	8,145	Lifestage Sex-Specific Genetic Effects on Metabolic Disorders in an Adult Population in Korea: The Korean Genome and Epidemiology Study.
GCST90244634	Kim YS	2022	1,306	9,901	Lifestage Sex-Specific Genetic Effects on Metabolic Disorders in an Adult Population in Korea: The Korean Genome and Epidemiology Study.
GCST90244632	Kim YS	2022	1,111	13,342	Lifestage Sex-Specific Genetic Effects on Metabolic Disorders in an Adult Population in Korea: The Korean Genome and Epidemiology Study.
GCST003743	Ram R	2016	927	3,159	A common variant association study in ethnic Saudi Arabs reveals novel susceptibility loci for hypertriglyceridemia.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	4
Tier 3: regulatory	2
Tier 4: intronic/intergenic	33

MAF distribution

Bucket	Variants
common (>=0.05)	43
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	15
intron_variant	14
missense_variant	3
splice_region_variant	2
non_coding_transcript_exon_variant	2
regulatory_region_variant	2
3_prime_UTR_variant	2
intron_variant; 3_prime_UTR_variant; intron_variant	1
stop_gained	1
intron_variant; intron_variant; intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs651821	11	116791863	C>A,T	0.05	splice_region_variant	APOA5	5e-228	Tier 2: splice/UTR
rs1260326	2	27508073	T>A,C,G	0.05	missense_variant	GCKR	1e-41	Tier 1: coding
rs438811	19	44913484	C>T	0.05	non_coding_transcript_exon_variant	APOC1	7e-37	Tier 4: intronic/intergenic
rs662799	11	116792991	G>A,C	0.278	regulatory_region_variant	APOA5	5e-34	Tier 3: regulatory
rs10503669	8	19990179	C>A,T	0.05	intergenic_variant	LPL - RPL30P9	3e-28	Tier 4: intronic/intergenic
rs7350481	11	116715567	T>A,C,G	0.05	intergenic_variant	LINC02702 - BUD13	2e-24	Tier 4: intronic/intergenic
rs1558861	11	116736721	C>G,T	0.05	intron_variant	LINC02702 - BUD13	4e-24	Tier 4: intronic/intergenic
rs964184	11	116778201	G>C	0.14	3_prime_UTR_variant	ZPR1	5e-24	Tier 2: splice/UTR
rs3825041	11;11;11	116760991	T>A,C,G	0.05	intron_variant; 3_prime_UTR_variant; intron_variant	BUD13; ZPR1; LINC02702 - BUD13	7e-20	Tier 4: intronic/intergenic
rs2954021	8	125469835	A>G	0.05	intron_variant	TRIB1AL	1e-19	Tier 4: intronic/intergenic
rs909267	6	31778771	T>C	0.05	intron_variant	VARS1	3e-16	Tier 4: intronic/intergenic
rs17145732	7	73555938	T>A,G	0.05	intron_variant	BCL7B	8e-15	Tier 4: intronic/intergenic
rs6589566	11	116781707	G>A,C,T	0.05	intron_variant	ZPR1	1e-14	Tier 4: intronic/intergenic
rs12037659	1	62458192	C>T	0.05	intron_variant	DOCK7	2e-14	Tier 4: intronic/intergenic
rs17145738	7	73568544	C>T	0.05	3_prime_UTR_variant	TBL2	2e-13	Tier 2: splice/UTR
rs780093	2	27519736	T>A,C,G	0.471	intron_variant	GCKR	3e-12	Tier 4: intronic/intergenic
rs671	12	111803962	G>A	0.05	missense_variant	ALDH2	7e-12	Tier 1: coding
rs72643559	11	61852802	T>C,G	0.05	intron_variant	FADS2	8e-10	Tier 4: intronic/intergenic
rs6531981	4	87362944	T>A,C	0.05	intron_variant	HSD17B11	9e-10	Tier 4: intronic/intergenic
rs58542926	19	19268740	C>A,T	0.05	stop_gained	TM6SF2	2e-09	Tier 1: coding
rs8033573	15	82765658	G>A	0.05	intron_variant	SNHG21, FSD2	9e-09	Tier 4: intronic/intergenic
rs780094	2	27518370	T>A,C,G	0.05	intron_variant	GCKR	2e-08	Tier 4: intronic/intergenic
rs6982502	8	125467120	C>T	0.05	intron_variant	TRIB1AL	2e-08	Tier 4: intronic/intergenic
rs738409	22	43928847	C>A,G,T	0.05	missense_variant	PNPLA3	3e-08	Tier 1: coding
rs4635554	2	21166787	T>G	0.31	intergenic_variant	TDRD15 - NUTF2P8	2e-07	Tier 4: intronic/intergenic
rs7016880	8	20019235	G>C	0.1	intergenic_variant	LPL - RPL30P9	2e-07	Tier 4: intronic/intergenic
rs10911205	1;1;1	183040142	C>A,G,T	0.05	intron_variant; intron_variant; intron_variant	LAMC1; LAMC2; LAMC1	2e-07	Tier 4: intronic/intergenic
rs1837842	8	20010779	T>C	0.05	intergenic_variant	LPL - RPL30P9	2e-07	Tier 4: intronic/intergenic
rs17411126	8	19997761	T>C	0.05	intergenic_variant	LPL - RPL30P9	2e-07	Tier 4: intronic/intergenic
rs7396835	11	116813312	T>A,C,G	0.05	non_coding_transcript_exon_variant	LNC-RHL1	2e-07	Tier 4: intronic/intergenic

ClinVar germline variants

8 retrieved; paginated sample, class counts are floors:

4 pathogenic, 2 conflicting classifications of pathogenicity, 1 uncertain significance, 1 likely 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
633592	NM_033440.3(CELA2A):c.361G>A (p.Asp121Asn)	CELA2A	Pathogenic	no assertion criteria provided
633594	NM_033440.3(CELA2A):c.639+1G>C	CELA2A	Pathogenic	no assertion criteria provided
633595	NM_033440.3(CELA2A):c.209C>T (p.Thr70Met)	CELA2A	Pathogenic	criteria provided, multiple submitters, no conflicts
633593	NM_033440.3(CELA2A):c.253C>A (p.Leu85Met)	CELA2A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
225370	NM_001486.4(GCKR):c.307G>A (p.Val103Met)	GCKR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
523886	NM_000237.3(LPL):c.784C>T (p.Gln262Ter)	LPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267924	46;XY;t(16;20)(q23.1;p11.22)		Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
APOA5	APOA5	GWAS, Orphanet
LPL	LPL	GWAS, Orphanet
MAP4K5	MAP4K5	GWAS

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
CREB3L3	Strong	Autosomal dominant	hypertriglyceridemia	4
LIPI	Limited	Autosomal dominant	hypertriglyceridemia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APOA5	Orphanet:530849	Familial apolipoprotein A5 deficiency
LPL	Orphanet:309015	Familial lipoprotein lipase deficiency
CREB3L3	Orphanet:300293	Transient infantile hypertriglyceridemia and hepatosteatosis
TBL2	Orphanet:904	Williams syndrome
APOA1	Orphanet:425	Apolipoprotein A-I deficiency
APOA1	Orphanet:93560	AApoAI amyloidosis
APOB	Orphanet:391665	Homozygous familial hypercholesterolemia

Cohort genes → proteins

14 cohort genes, 14 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	7
gwas_and_clinvar	3
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APOA5	HGNC:17288	ENSG00000110243	Q6Q788	Apolipoprotein A-V	gwas,clinvar
LPL	HGNC:6677	ENSG00000175445	P06858	Lipoprotein lipase	gwas,clinvar
MAP4K5	HGNC:6867	ENSG00000012983	Q9Y4K4	Mitogen-activated protein kinase kinase kinase kinase 5	gwas,clinvar
LIPI	HGNC:18821	ENSG00000188992	Q6XZB0	Lipase member I	gencc
CREB3L3	HGNC:18855	ENSG00000060566	Q68CJ9	Cyclic AMP-responsive element-binding protein 3-like protein 3	gencc
TBL2	HGNC:11586	ENSG00000106638	Q9Y4P3	Transducin beta-like protein 2	gwas
MLXIPL	HGNC:12744	ENSG00000009950	Q9NP71	Carbohydrate-responsive element-binding protein	gwas
TRIB1	HGNC:16891	ENSG00000173334	Q96RU8	Tribbles homolog 1	gwas
CELA2A	HGNC:24609	ENSG00000142615	P08217	Chymotrypsin-like elastase family member 2A	clinvar
BUD13	HGNC:28199	ENSG00000137656	Q9BRD0	BUD13 homolog	gwas
GCKR	HGNC:4196	ENSG00000084734	Q14397	Glucokinase regulatory protein	clinvar
APOA1	HGNC:600	ENSG00000118137	P02647	Apolipoprotein A-I	gwas
APOB	HGNC:603	ENSG00000084674	P04114	Apolipoprotein B-100	gwas
LAMC1	HGNC:6492	ENSG00000135862	P11047	Laminin subunit gamma-1	gwas

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.
LPL	Lipoprotein lipase	Key enzyme in triglyceride metabolism.
MAP4K5	Mitogen-activated protein kinase kinase kinase kinase 5	May play a role in the response to environmental stress.
LIPI	Lipase member I	Hydrolyzes specifically phosphatidic acid (PA) to produce 2-acyl lysophosphatidic acid (LPA; a potent bioactive lipid mediator) and fatty acid.
CREB3L3	Cyclic AMP-responsive element-binding protein 3-like protein 3	Transcription factor that may act during endoplasmic reticulum stress by activating unfolded protein response target genes.
MLXIPL	Carbohydrate-responsive element-binding protein	Glucose-responsive transcription activator that regulates fatty acid synthesis and glycolysis.
TRIB1	Tribbles homolog 1	Adapter protein involved in protein degradation by interacting with COP1 ubiquitin ligase.
CELA2A	Chymotrypsin-like elastase family member 2A	Elastase that enhances insulin signaling and might have a physiologic role in cellular glucose metabolism.
BUD13	BUD13 homolog	Involved in pre-mRNA splicing as component of the activated spliceosome.
GCKR	Glucokinase regulatory protein	Regulates glucokinase (GCK) by forming an inactive complex with this enzyme.
APOA1	Apolipoprotein A-I	Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol acyltransferase (LCAT).
APOB	Apolipoprotein B-100	Apolipoprotein B is a major protein constituent of chylomicrons (apo B-48), LDL (apo B-100) and VLDL (apo B-100).
LAMC1	Laminin subunit gamma-1	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.

Protein-family classification

Druggable: 6 · Difficult: 2 · Unknown: 6 · Druggable fraction: 0.43

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
Kinase	3	5.9×	0.076
Protease	1	2.6×	0.656
Enzyme (other)	2	1.7×	0.656
Scaffold/PPI	1	1.2×	0.849
Other/Unknown	6	0.8×	0.893
Transcription factor	1	0.6×	0.893

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APOA5	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
LPL	Enzyme (other)	yes	3.1.1.34	TAG_lipase, PLAT/LH2_dom, Lipo_Lipase
MAP4K5	Kinase	yes		Prot_kinase_dom, CNH_dom, Kinase-like_dom_sf
LIPI	Enzyme (other)	yes	3.1.1.111	TAG_lipase, Lipase, Lipase_LIPH
CREB3L3	Other/Unknown	no		bZIP, bZIP_sf, CREB_ATF_subfamily
TBL2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_PAC1
MLXIPL	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, Max-like/E-box_TFs
TRIB1	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Tribbles/Ser_Thr_kinase_40
CELA2A	Protease	yes		Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
BUD13	Other/Unknown	no		Bud13, CWC26_splicing_factor
GCKR	Kinase	yes		SIS_dom, Glucokinase_regulatory_CS, MURQ/GCKR
APOA1	Other/Unknown	no		ApoA_E, Apolipoprotein_A1/A4/E
APOB	Other/Unknown	no		Vitellogenin_N, Lipid_transpt_open_b-sht, Lipovitellin_superhlx_dom
LAMC1	Other/Unknown	no		Laminin_IV, EGF, LE_dom

Expression context

Cohort genes with no expression data: 0.

12 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)	14
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	5
liver	4
jejunal mucosa	3
left adrenal gland cortex	2
visceral pleura	2
skeletal muscle tissue of rectus abdominis	1
dorsal root ganglion	1
olfactory bulb	1
trigeminal ganglion	1
calcaneal tendon	1
corpus callosum	1
sural nerve	1
cauda epididymis	1
corpus epididymis	1
male germ line stem cell (sensu Vertebrata) in testis	1
duodenum	1
adult organism	1
left testis	1
right testis	1
right adrenal gland	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
LPL	272	broad	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion
MAP4K5	296	ubiquitous	marker	corpus callosum, sural nerve, calcaneal tendon
LIPI	102	tissue_specific	marker	corpus epididymis, male germ line stem cell (sensu Vertebrata) in testis, cauda epididymis
CREB3L3	119	tissue_specific	marker	right lobe of liver, jejunal mucosa, duodenum
TBL2	292	ubiquitous	marker	adult organism, left testis, right testis
MLXIPL	203	broad	marker	right lobe of liver, right adrenal gland, left adrenal gland cortex
TRIB1	280	ubiquitous	marker	mucosa of urinary bladder, mucosa of sigmoid colon, visceral pleura
CELA2A	128	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans
BUD13	246	ubiquitous	marker	secondary oocyte, oocyte, tendon of biceps brachii
GCKR	165	tissue_specific	yes	right lobe of liver, liver, left adrenal gland cortex
APOA1	170	broad	marker	jejunal mucosa, right lobe of liver, liver
APOB	116	broad	marker	jejunal mucosa, liver, ileal mucosa
LAMC1	292	ubiquitous	marker	stromal cell of endometrium, visceral pleura, parietal pleura

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APOB	5,244
APOA1	3,608
TBL2	2,770
LAMC1	2,573
TRIB1	2,326
LPL	2,149
BUD13	2,107
APOA5	1,919
MLXIPL	1,659
CREB3L3	1,421

Intra-cohort edges

A	B	Sources
APOA1	APOB	string_interaction
APOA5	APOB	string_interaction
APOA5	BUD13	string_interaction
APOA5	CREB3L3	string_interaction
APOA5	LIPI	string_interaction
APOA5	LPL	intact, string_interaction
APOA5	TRIB1	string_interaction
APOB	LPL	string_interaction
APOB	TRIB1	string_interaction
MLXIPL	TBL2	string_interaction
MLXIPL	TRIB1	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APOA1	P02647	31
GCKR	Q14397	18
BUD13	Q9BRD0	11
APOB	P04114	8
MLXIPL	Q9NP71	7
LPL	P06858	5
TRIB1	Q96RU8	5
LAMC1	P11047	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CELA2A	P08217	93.66
LIPI	Q6XZB0	89.19
TBL2	Q9Y4P3	87.11
MAP4K5	Q9Y4K4	74.15
APOA5	Q6Q788	72.38
CREB3L3	Q68CJ9	60.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 109. Enrichment computed across 14 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Chylomicron remodeling	4	380.7×	2e-08	APOA5, LPL, APOA1, APOB
Plasma lipoprotein remodeling	4	158.6×	4e-07	APOA5, LPL, APOA1, APOB
Plasma lipoprotein assembly, remodeling, and clearance	4	76.1×	6e-06	APOA5, LPL, APOA1, APOB
Assembly of active LPL and LIPC lipase complexes	3	150.3×	2e-05	APOA5, LPL, CREB3L3
Metabolism of fat-soluble vitamins	3	95.2×	8e-05	LPL, APOA1, APOB
Post-translational protein phosphorylation	4	33.4×	8e-05	APOA5, APOA1, APOB, LAMC1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	4	28.8×	1e-04	APOA5, APOA1, APOB, LAMC1
Visual phototransduction	3	64.9×	2e-04	LPL, APOA1, APOB
Retinoid metabolism and transport	3	62.1×	2e-04	LPL, APOA1, APOB
Chylomicron assembly	2	190.3×	5e-04	APOA1, APOB
Scavenging by Class B Receptors	2	173.0×	5e-04	APOA1, APOB
Plasma lipoprotein assembly	2	119.0×	0.001	APOA1, APOB
Metabolism of vitamins and cofactors	3	29.1×	0.001	LPL, APOA1, APOB
Scavenging by Class A Receptors	2	100.2×	0.001	APOA1, APOB
Binding and Uptake of Ligands by Scavenger Receptors	2	90.6×	0.002	APOA1, APOB
Sensory Perception	3	23.8×	0.002	LPL, APOA1, APOB
Metabolism	6	5.8×	0.002	APOA5, LPL, MLXIPL, LIPI, APOA1, APOB
Plasma lipoprotein clearance	2	79.3×	0.002	APOA1, APOB
Transport of small molecules	4	8.4×	0.005	APOA5, LPL, APOA1, APOB
Heme signaling	2	35.9×	0.007	APOA1, APOB
Defective ABCA1 causes TGD	1	475.8×	0.011	APOA1
Post-translational protein modification	4	6.4×	0.013	APOA5, APOA1, APOB, LAMC1
Regulation of lipid metabolism by PPARalpha	2	23.5×	0.015	APOA5, APOA1
Scavenging by Class H Receptors	1	237.9×	0.019	APOB
PKA-mediated phosphorylation of key metabolic factors	1	190.3×	0.020	MLXIPL
VLDL assembly	1	190.3×	0.020	APOB
HDL clearance	1	190.3×	0.020	APOA1
Chylomicron clearance	1	190.3×	0.020	APOB
Metabolism of lipids	3	7.9×	0.021	APOA5, LIPI, APOA1
Scavenging by Class F Receptors	1	158.6×	0.021	APOB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
triglyceride homeostasis	5	172.0×	1e-08	APOA5, LPL, MLXIPL, GCKR, APOA1
triglyceride catabolic process	3	172.0×	5e-05	APOA5, LPL, APOB
cholesterol homeostasis	4	44.6×	9e-05	APOA5, LPL, APOA1, APOB
cholesterol efflux	3	112.8×	9e-05	APOA5, APOA1, APOB
very-low-density lipoprotein particle clearance	2	481.5×	2e-04	APOA5, LPL
acylglycerol homeostasis	2	481.5×	2e-04	APOA5, APOA1
cellular response to lipoprotein particle stimulus	2	481.5×	2e-04	APOA1, APOB
lipoprotein biosynthetic process	2	401.2×	2e-04	APOA1, APOB
positive regulation of cholesterol storage	2	343.9×	3e-04	LPL, APOB
positive regulation of lipid storage	2	200.6×	7e-04	LPL, APOB
cholesterol metabolic process	3	42.0×	7e-04	APOA5, APOA1, APOB
positive regulation of fatty acid biosynthetic process	2	185.2×	7e-04	APOA5, MLXIPL
phospholipid efflux	2	160.5×	9e-04	APOA5, APOA1
positive regulation of macrophage derived foam cell differentiation	2	120.4×	0.001	LPL, APOB
high-density lipoprotein particle remodeling	2	114.6×	0.001	LPL, APOA1
cholesterol transport	2	104.7×	0.002	APOA1, APOB
triglyceride metabolic process	2	63.4×	0.004	APOA5, LPL
carbohydrate derivative metabolic process	1	1203.7×	0.008	GCKR
response to glucose	2	36.5×	0.012	LPL, GCKR
positive regulation of very-low-density lipoprotein particle remodeling	1	601.9×	0.013	APOA5
positive regulation of eosinophil differentiation	1	601.9×	0.013	TRIB1
negative regulation of neutrophil differentiation	1	601.9×	0.013	TRIB1
protein oxidation	1	401.2×	0.015	APOA1
peptidyl-methionine modification	1	401.2×	0.015	APOA1
negative regulation of glucokinase activity	1	401.2×	0.015	GCKR
triglyceride-rich lipoprotein particle remodeling	1	401.2×	0.015	APOA5
low-density lipoprotein particle mediated signaling	1	401.2×	0.015	LPL
triglyceride mobilization	1	300.9×	0.017	APOB
regulation of intestinal cholesterol absorption	1	300.9×	0.017	APOA1
chylomicron remodeling	1	300.9×	0.017	LPL

Therapeutics

Drugs indicated for this disease

1 approved, 18 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Icosapent Ethyl	Approved (phase 4)
Atorvastatin	Phase 3 (in late-stage trials)
Ciprofloxacin	Phase 3 (in late-stage trials)
Corn Oil	Phase 3 (in late-stage trials)
Ezetimibe	Phase 3 (in late-stage trials)
Fenofibrate	Phase 3 (in late-stage trials)
Fenofibric Acid	Phase 3 (in late-stage trials)
Icosapent	Phase 3 (in late-stage trials)
K-877	Phase 3 (in late-stage trials)
OMEGA-3-ACID ETHYL ESTERS	Phase 3 (in late-stage trials)
OMEGA-3-CARBOXYLIC ACIDS	Phase 3 (in late-stage trials)
OMEGA-3-PENTAENOIC ACIDS	Phase 3 (in late-stage trials)
Olezarsen	Phase 3 (in late-stage trials)
Olive Oil	Phase 3 (in late-stage trials)
Pegozafermin	Phase 3 (in late-stage trials)
Simvastatin	Phase 3 (in late-stage trials)
Topiramate	Phase 3 (in late-stage trials)
Torcetrapib	Phase 3 (in late-stage trials)
Volanesorsen	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Evinacumab.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 12

Druggability breadth: 7 of 14 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
LPL	ORLISTAT
MAP4K5	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP4K5	67	4
LPL	1	4
APOA5	0	0
LIPI	0	0
CREB3L3	0	0
TBL2	0	0
MLXIPL	0	0
TRIB1	0	0
CELA2A	0	0
BUD13	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ORLISTAT	4	LPL
VEMURAFENIB	4	MAP4K5
LENVATINIB	4	MAP4K5
AXITINIB	4	MAP4K5
SORAFENIB	4	MAP4K5
NERATINIB	4	MAP4K5
PALBOCICLIB	4	MAP4K5
ENTRECTINIB	4	MAP4K5
VANDETANIB	4	MAP4K5
BOSUTINIB	4	MAP4K5
GILTERITINIB	4	MAP4K5
PAZOPANIB	4	MAP4K5
NINTEDANIB	4	MAP4K5
SUNITINIB	4	MAP4K5
DASATINIB	4	MAP4K5
QUIZARTINIB	4	MAP4K5
CRIZOTINIB	4	MAP4K5
MIDOSTAURIN	4	MAP4K5
GEFITINIB	4	MAP4K5
LINSITINIB	3	MAP4K5
DACTOLISIB	3	MAP4K5
CRENOLANIB	3	MAP4K5
SARACATINIB	3	MAP4K5
LINIFANIB	3	MAP4K5
CANERTINIB	3	MAP4K5
TESEVATINIB	3	MAP4K5
BRIVANIB	3	MAP4K5
BARASERTIB	3	MAP4K5
CEDIRANIB	3	MAP4K5
DOVITINIB	3	MAP4K5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
MAP4K5	262	Binding:261, Functional:1
LPL	16	Binding:16
GCKR	16	Binding:16
APOA1	2	Binding:2
TBL2	1	Binding:1
TRIB1	1	Binding:1
APOB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LPL	3.1.1.34	lipoprotein lipase
LIPI	3.1.1.111, 3.1.1.32	phosphatidylserine sn-1 acylhydrolase, phospholipase A1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MAP4K5	262

Pharmacogenomics

Cohort genes with a PharmGKB record: 14; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
VEMURAFENIB	4	MAP4K5
LENVATINIB	4	MAP4K5
AXITINIB	4	MAP4K5
SORAFENIB	4	MAP4K5
NERATINIB	4	MAP4K5
PALBOCICLIB	4	MAP4K5
ENTRECTINIB	4	MAP4K5
VANDETANIB	4	MAP4K5
BOSUTINIB	4	MAP4K5
GILTERITINIB	4	MAP4K5
PAZOPANIB	4	MAP4K5
NINTEDANIB	4	MAP4K5
SUNITINIB	4	MAP4K5
DASATINIB	4	MAP4K5
QUIZARTINIB	4	MAP4K5
CRIZOTINIB	4	MAP4K5
MIDOSTAURIN	4	MAP4K5
GEFITINIB	4	MAP4K5
LINSITINIB	3	MAP4K5
DACTOLISIB	3	MAP4K5
CRENOLANIB	3	MAP4K5
SARACATINIB	3	MAP4K5
LINIFANIB	3	MAP4K5
CANERTINIB	3	MAP4K5
TESEVATINIB	3	MAP4K5
BRIVANIB	3	MAP4K5
BARASERTIB	3	MAP4K5
CEDIRANIB	3	MAP4K5
DOVITINIB	3	MAP4K5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	LPL, MAP4K5
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	TRIB1, GCKR
D	Druggable family + AlphaFold only, no drug	2	LIPI, CELA2A
E	Difficult family or no structure, no drug	8	APOA5, CREB3L3, TBL2, MLXIPL, BUD13, APOA1, APOB, LAMC1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
APOA5	0	—
LIPI	0	—
CREB3L3	0	—
TBL2	1	—
MLXIPL	0	—
TRIB1	1	—
CELA2A	0	—
BUD13	0	—
GCKR	16	—
APOA1	2	—
APOB	1	—
LAMC1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 232.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	79
PHASE3	45
PHASE2	44
PHASE4	28
PHASE1	21
PHASE1/PHASE2	7
PHASE2/PHASE3	5
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00246636	PHASE4	COMPLETED	Evaluation of Efficacy and Safety of Omacor (Omega-3-acid Ethyl Esters) as Add-on Therapy in Hypertriglyceridemic Subjects Treated With Antara (Fenofibrate) Followed by an 8-week Extension
NCT00286234	PHASE4	COMPLETED	Niacin, N-3 Fatty Acids and Insulin Resistance
NCT00346697	PHASE4	COMPLETED	Omega-3 Fatty Acids for High Triglycerides in HIV-infected Patients
NCT00397358	PHASE4	WITHDRAWN	Effect of Extraneal (Icodextrin)on Triglyceride Levels in PD Patients
NCT00473655	PHASE4	COMPLETED	Effect of Rosuvastatin on Triglyceride Levels in Mexican Hypertriglyceridemic Patients
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00745407	PHASE4	COMPLETED	Effects of Fenofibrate on Adipocytokine Levels In Hypertriglyceridemic Patients
NCT00758927	PHASE4	UNKNOWN	The Effects of Omega-3 Fatty Acid (OMACOR) on the Low-density Lipoprotein (LDL) Sub-fraction in Type 2 Diabetic Patients
NCT00891293	PHASE4	COMPLETED	A Second Open-Label Extension of a Double-Blind, Parallel, Phase IV Study to Assess the Efficacy and Safety of Adjunctive Lovaza® (Formerly Known as Omacor®) Therapy in Hypertriglyceridemic Subjects Treated With Antara™
NCT00931879	PHASE4	COMPLETED	Lovaza® and Microvascular Function in Type 2 Diabetes
NCT00934219	PHASE4	UNKNOWN	Triglyceride Lowering Study
NCT01003847	PHASE4	COMPLETED	Differential Metabolic Effects of Fenofibrate and Fatty Acid
NCT01010399	PHASE4	COMPLETED	Boosted Lexiva With Lovaza Adjunctive Therapy in Hypertriglyceridemic, HIV-Infected Subjects
NCT01180764	PHASE4	WITHDRAWN	Effects of Lovaza on High Density Lipoprotein (HDL) Composition and Function in Hypertriglyceridemia
NCT01462877	PHASE4	COMPLETED	A Study to Evaluate Fenofibrate Combination With Statin in Chinese Patients With Dyslipidemic
NCT01480687	PHASE4	UNKNOWN	Fish Oil Supplementation and Vascular Function in Hypertensive Patients With Hypertriglyceridemia
NCT01527747	PHASE4	SUSPENDED	Effects of DPP-4 Inhibition on Triglycerides
NCT01569724	PHASE4	COMPLETED	Carbohydrate Metabolism Disorder Frequency in Hypertriglyceridemia Induced by Bexarotene of Cutaneous T Cell Lymphoma
NCT01625442	PHASE4	COMPLETED	Crocus Sativus (Saffron) and Berberis Vulgaris (Barberry Fruit) in Metabolic Syndrome
NCT01660932	PHASE4	COMPLETED	Vascular and Metabolic Effects of Omega-3 Fatty Acids
NCT01666041	PHASE4	COMPLETED	Vascular and Metabolic Effects of Fenofibrate/Omega vs Fenofibrate
NCT02015988	PHASE4	UNKNOWN	Simvastatin and Fenofibrate vs Simvastatin Alone in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome
NCT02926027	PHASE4	COMPLETED	Effect of Vascepa on Improving Coronary Atherosclerosis in People With High Triglycerides Taking Statin Therapy
NCT03120299	PHASE4	COMPLETED	The Effect of Omega-3 FA on Hypertriglyceridemia in Patients With T2DM(OCEAN)
NCT03342807	PHASE4	UNKNOWN	Intravenous Administration of Insulin and Plasma Exchange on Triglyceride Levels in Early Stage of Hypertriglyceridemia-induced Pancreatitis
NCT03501680	PHASE4	UNKNOWN	Intensive Insulin for Severe/Moderate Hypertriglyceridemia Pancreatitis.
NCT05487833	PHASE4	UNKNOWN	Insulin and Standard Management in Hypertriglyceridemic Acute Pancreatitis
NCT06129526	PHASE4	UNKNOWN	Study of the Efficacy and Safety of EPA in Patients With Type-2 Diabetes
NCT05681351	PHASE3	ACTIVE_NOT_RECRUITING	CORE-OLE: A Study of Olezarsen (ISIS 678354) Administered Subcutaneously to Participants With Severe Hypertriglyceridemia (SHTG)
NCT05852431	PHASE3	ACTIVE_NOT_RECRUITING	To Evaluate the Efficacy and Safety of Pegozafermin in Subjects With Severe Hypertriglyceridemia
NCT06220266	PHASE2/PHASE3	RECRUITING	Effects of Phytoestrogen From Pueraria Mirifica in Improvement of Serum Lipid Parameters in Postmenopausal Women
NCT06347003	PHASE3	ACTIVE_NOT_RECRUITING	Study of Plozasiran (ARO-APOC3) in Adults With Severe Hypertriglyceridemia
NCT06347016	PHASE3	ACTIVE_NOT_RECRUITING	Study of Plozasiran in Adults With Severe Hypertriglyceridemia
NCT06347133	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Study of Plozasiran in Adults With Hypertriglyceridemia
NCT06822790	PHASE3	RECRUITING	Long-Term Safety and Efficacy of Plozasiran in Adults With Hypertriglyceridemia
NCT06880770	PHASE3	RECRUITING	Study of Plozasiran in Adults With Severe Hypertriglyceridemia at Risk of Acute Pancreatitis
NCT07349615	PHASE3	NOT_YET_RECRUITING	A Study of SHR-1918 In Participants With Hypertriglyceridemia
NCT00092560	PHASE3	COMPLETED	Two Investigational Drugs in Patients With Mixed Hyperlipidemia (0653-036)
NCT00092573	PHASE3	COMPLETED	Study of Ezetimibe and Fenofibrate in Patients With Mixed Hyperlipidemia (0653-036)(COMPLETED)
NCT00093899	PHASE3	COMPLETED	A Study to Evaluate an Investigational Drug in Patients With Mixed Hyperlipidemia (0653A-071)(COMPLETED)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OMEGA-3-ACID ETHYL ESTERS	4	18
FENOFIBRATE	4	16
FISH OIL	4	4
OMEGA-3-CARBOXYLIC ACIDS	4	4
ICOSAPENT ETHYL	4	3
SAXAGLIPTIN ANHYDROUS	4	3
ACIPIMOX	4	2
EVINACUMAB	4	2
EZETIMIBE	4	2
NIACIN	4	2
OLIVE OIL	4	2
ROSUVASTATIN	4	2
AMINO ACIDS	4	1
ARTENIMOL	4	1
ATORVASTATIN	4	1
CHENODIOL	4	1
CIPROFIBRATE	4	1
FENOFIBRIC ACID	4	1
FOSAMPRENAVIR	4	1
GEMFIBROZIL	4	1
ICODEXTRIN	4	1
INSULIN HUMAN	4	1
MARAVIROC	4	1
ORLISTAT	4	1
RALTEGRAVIR	4	1
RITONAVIR	4	1
SETMELANOTIDE	4	1
SIMVASTATIN	4	1
TELMISARTAN	4	1
TOPIRAMATE	4	1