Familial hyperlipidemia

Summary

Familial hyperlipidemia (MONDO:0001336) is a disease (an umbrella term covering 10 Mondo subtypes) with 229 GWAS associations across 5 studies and 22 clinical trials. Top therapeutic interventions include rosuvastatin, ezetimibe, and ongericimab. A subtype of inherited lipid metabolism disorder — broader associated-gene and molecular evidence is on the parent page (see Disease family below).

At a glance

• Umbrella term: 10 Mondo subtypes
• GWAS associations: 229
• Clinical trials: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hyperlipidemia
Mondo ID	MONDO:0001336
DOID	DOID:1168
UMLS	C0700623
MedGen	675194
GARD	0022924
Is cancer (heuristic)	no

Also known as: hereditary hyperlipidemia (disease) · hyperlipemia · hyperlipidaemia

Data availability: 229 GWAS associations (5 studies).

Disease family

This is a subtype of inherited lipid metabolism disorder. Genetic, therapeutic, and trial evidence is largely curated at the broader-term level — see the parent page for the associated-gene cohort and molecular evidence.

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

Related subtypes (28): cortisone reductase deficiency, hypolipoproteinemia, steroid inherited metabolic disorder, corticosterone methyloxidase type 1 deficiency, lipoid proteinosis, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, vitamin D hydroxylation-deficient rickets, type 1B, mitochondrial trifunctional protein deficiency, pancreatic triacylglycerol lipase deficiency, glucocorticoid resistance, syndromic dyslipidemia, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of plasmalogens biosynthesis, disorder of phospholipids, sphingolipids and fatty acids biosynthesis, inborn disorder of ketolysis, lysosomal lipid storage disorder, sterol metabolism disorder, disorder of sphingolipid biosynthesis, glycosylphosphatidylinositol biosynthesis defect 18, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 55, inherited fatty acid metabolism disorder, glycosylphosphatidylinositol biosynthesis defect 16, glycosylphosphatidylinositol biosynthesis defect 15, glycosylphosphatidylinositol biosynthesis defect 17, CYP7B1-related disorder of oxysterol accumulation

Subtypes (10): 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, hyperlipoproteinemia type 3

Genetics & variants

GWAS landscape

229 GWAS associations across 5 studies. Top hits map to 30 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs429358	3e-226	APOE	T	0.32
rs964184	9e-180	ZPR1	G	0.43
rs12740374	7e-175	CELSR2	G	0.27
rs28601761	1e-135	TRIB1AL	C	0.2
rs1065853	1e-121	APOE - APOC1	G	0.55
rs6511720	1e-110	LDLR	G	0.28
rs1260326	4e-92	GCKR	T	0.23
rs952275	1e-91	LINC02850 - APOB	T	0.16
rs11591147	9e-76	PCSK9	G	0.62
rs10401176	1e-69	BCL3	C	0.21
rs17091891	3e-64	LPL - RPL30P9	T	0.31
rs503662	3e-55	TDRD15 - NUTF2P8	T	0.14
rs17410962	3e-54	LPL - RPL30P9	G	0.19
rs1748199	7e-51	DOCK7	T	0.12
rs1168132	5e-49	DOCK7	T	0.17
rs58542926	4e-42	TM6SF2	C	0.21
rs74617384	4e-39	LPA	A	0.18
rs4299376	7e-35	ABCG8	G	0.1
rs7841189	6e-34	LPL - RPL30P9	C	0.42
rs13240994	4e-32	MLXIPL	T	0.17
rs16996148	2e-31	CILP2 - PBX4	G	0.17
rs13167071	6e-29	TIMD4	G	0.09
rs3125050	8e-26	SLC22A2 - SLC22A3	A	0.11
rs4635554	3e-25	TDRD15 - NUTF2P8	T	0.12
rs1811376	2e-23	SLC44A2	G	0.16
rs1168124	9e-23	DOCK7	C	0.24
rs540662190	1e-20	ERCC1, POLR1G	C	0.32
rs998584	5e-20	VEGFA - LINC02537	C	0.07
rs35368205	9e-20	MLXIPL	C	0.24
rs60960031	2e-19	TDRD15 - NUTF2P8	G	0.07

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90104006	Trinder M	2021	39,961	309,261	Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia.
GCST90104005	Trinder M	2021	17,485	331,737	Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia.
GCST90104007	Trinder M	2021	5,153	344,069	Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia.
GCST90104003	Trinder M	2021	3,838	345,384	Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia.
GCST90104004	Trinder M	2021	1,688	347,534	Polygenic architecture and cardiovascular risk of familial combined hyperlipidemia.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	6
Tier 3: regulatory	2
Tier 4: intronic/intergenic	38

MAF distribution

Bucket	Variants
common (>=0.05)	46
low_freq (0.01-0.05)	4
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	26
intergenic_variant	11
3_prime_UTR_variant	5
missense_variant	3
regulatory_region_variant	2
non_coding_transcript_exon_variant	1
stop_gained	1
5_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs429358	19	44908684	T>C	0.156	missense_variant	APOE	3e-226	Tier 1: coding
rs964184	11	116778201	G>C	0.132	3_prime_UTR_variant	ZPR1	9e-180	Tier 2: splice/UTR
rs12740374	1	109274968	G>T	0.222	3_prime_UTR_variant	CELSR2	7e-175	Tier 2: splice/UTR
rs28601761	8	125487789	C>G	0.419	intron_variant	TRIB1AL	1e-135	Tier 4: intronic/intergenic
rs1065853	19	44909976	G>A,C,T	0.08	non_coding_transcript_exon_variant	APOE - APOC1	1e-121	Tier 4: intronic/intergenic
rs6511720	19	11091630	G>T	0.118	intron_variant	LDLR	1e-110	Tier 4: intronic/intergenic
rs1260326	2	27508073	T>A,C,G	0.394	missense_variant	GCKR	4e-92	Tier 1: coding
rs952275	2	20998527	T>A,G	0.476	intergenic_variant	LINC02850 - APOB	1e-91	Tier 4: intronic/intergenic
rs11591147	1	55039974	G>A,T	0.018	missense_variant	PCSK9	9e-76	Tier 1: coding
rs10401176	19	44750234	C>G,T	0.125	intron_variant	BCL3	1e-69	Tier 4: intronic/intergenic
rs17091891	8	19985660	T>A,C	0.118	intergenic_variant	LPL - RPL30P9	3e-64	Tier 4: intronic/intergenic
rs503662	2	21191270	T>A,C,G	0.246	intergenic_variant	TDRD15 - NUTF2P8	3e-55	Tier 4: intronic/intergenic
rs17410962	8	19990569	G>A	0.118	intergenic_variant	LPL - RPL30P9	3e-54	Tier 4: intronic/intergenic
rs1748199	1	62591465	T>A,C	0.354	intron_variant	DOCK7	7e-51	Tier 4: intronic/intergenic
rs1168132	1	62667797	T>A,C	0.354	intron_variant	DOCK7	5e-49	Tier 4: intronic/intergenic
rs58542926	19	19268740	C>A,T	0.075	stop_gained	TM6SF2	4e-42	Tier 1: coding
rs74617384	6	160576086	A>C,G,T	0.08	intron_variant	LPA	4e-39	Tier 4: intronic/intergenic
rs4299376	2	43845437	G>C,T	0.324	intron_variant	ABCG8	7e-35	Tier 4: intronic/intergenic
rs7841189	8	19987865	C>G,T	0.118	intergenic_variant	LPL - RPL30P9	6e-34	Tier 4: intronic/intergenic
rs13240994	7	73602532	T>C	0.199	intron_variant	MLXIPL	4e-32	Tier 4: intronic/intergenic
rs16996148	19	19547663	G>T	0.082	intergenic_variant	CILP2 - PBX4	2e-31	Tier 4: intronic/intergenic
rs13167071	5	156946626	G>A,C	0.361	intron_variant	TIMD4	6e-29	Tier 4: intronic/intergenic
rs3125050	6	160319804	A>C,G	0.157	intergenic_variant	SLC22A2 - SLC22A3	8e-26	Tier 4: intronic/intergenic
rs4635554	2	21166787	T>G	0.338	intergenic_variant	TDRD15 - NUTF2P8	3e-25	Tier 4: intronic/intergenic
rs1811376	19	10640404	G>A,C,T	0.07	intron_variant	SLC44A2	2e-23	Tier 4: intronic/intergenic
rs1168124	1	62674059	C>A,G,T	0.351	intron_variant	DOCK7	9e-23	Tier 4: intronic/intergenic
rs540662190	19	45409992	C>A,T	0.016	3_prime_UTR_variant	ERCC1, POLR1G	1e-20	Tier 2: splice/UTR
rs998584	6	43790159	C>A,G,T	0.482	regulatory_region_variant	VEGFA - LINC02537	5e-20	Tier 3: regulatory
rs35368205	7	73603327	C>T	0.199	intron_variant	MLXIPL	9e-20	Tier 4: intronic/intergenic
rs60960031	2	21307787	G>A,C	0.401	intron_variant	TDRD15 - NUTF2P8	2e-19	Tier 4: intronic/intergenic

Genes & proteins

No associated-gene cohort resolved for this disease. Atlas builds the molecular and therapeutic sections — associated genes, protein families, druggability, pathways, interactions, and drug associations — by aggregating over a disease’s associated genes (resolved via GWAS / GenCC / ClinVar / CIViC), and none resolved here. This is expected for antibody-mediated, autoimmune, or otherwise non-gene-defined conditions; the curated evidence for this disease is its clinical features, GWAS susceptibility, and clinical trials (above).

Function

No pathway enrichment — requires an associated-gene cohort.

Therapeutics

No druggable-target or therapeutic data for this disease’s cohort.

Clinical trials & evidence

Clinical trials

Clinical trials: 22.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE3	3
PHASE2	3
PHASE1	3
PHASE4	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02593487	PHASE4	UNKNOWN	Effect of Rosuvastatin Therapy on HDL2 Level
NCT00328523	PHASE3	COMPLETED	TWICE (Ezetimibe Together With Any Statin Cholesterol Enhancement)(0653-060)
NCT04781114	PHASE3	COMPLETED	The Safety and Efficacy of Multiple-dose of JS002 in Subject With Hyperlipidemia
NCT05532800	PHASE3	COMPLETED	The Efficacy and Safety of JS002 PFS and AI in Patients With Primary Hypercholesterolemia and Mixed Hyperlipidemia
NCT07025980	PHASE2	NOT_YET_RECRUITING	Effect of Sinbiotic With Multispecies Probiotics on Liver Parameters Liver Enzymes, Ultrasound, Elastography and Adipokines in Same Cases) in Patients With Metabolic Associated Steatotic Liver Disease.
NCT04469673	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety, Tolerability and Efficacy of Multiple Doses of JS002 in Patients With Hyperlipidemia..
NCT04515927	PHASE2	COMPLETED	To Evaluate the Efficacy and Safety of JS002 in HoFH Patients
NCT04964557	PHASE2	COMPLETED	A Study to Assess the Safety, Efficacy and Tolerability of AZD8233 Treatment in Participants With Hyperlipidaemia
NCT05432544	PHASE1	UNKNOWN	Safety and Tolerability of SHR-1918 in Healthy Subjects
NCT05912296	PHASE1	COMPLETED	A Single and Multiple Ascending Doses Study to Evaluate the Safety, Tolerability and Pharmacokinetics of RBD7022
NCT06229548	PHASE1	COMPLETED	A Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SYH2053
NCT07036471	Not specified	NOT_YET_RECRUITING	Supporting Patients Starting New Medicines: Evaluating the myCare Start Service in Switzerland
NCT07037563	Not specified	RECRUITING	Developing an AI Pharmacy Chatbot for the Population of Hong Kong
NCT07316075	Not specified	ENROLLING_BY_INVITATION	Multicenter Study on Cardiovascular and Metabolic Complications in Patients With Biochemically Silent Pheochromocytomas and Paragangliomas
NCT07339852	Not specified	RECRUITING	Implementation and Evaluation of a Pharmacist-led Diabetes Care Pathway in Alberta Community Pharmacies
NCT02697422	Not specified	COMPLETED	Veteran Peer Coaches Optimizing and Advancing Cardiac Health
NCT03950752	Not specified	COMPLETED	Effect of Consumption of Bagel Without Palm Oil on Postprandial Lipidemia
NCT04382521	Not specified	COMPLETED	A Text Message Intervention to Promote Health Behaviors in Cardiac Risk Conditions
NCT05233917	Not specified	COMPLETED	Effects of Olive Oil and MLCT on Glycolipid Homeostasis in Patients With Metabolic Syndrome
NCT05767996	Not specified	UNKNOWN	School-based Education and Screening Program With Lipid Screening as a Means to Identify Familial Hyperlipidemia
NCT05814419	Not specified	COMPLETED	Familial Hyperlipidemia Family Registry
NCT06890546	Not specified	COMPLETED	Nigella Sativa Supplementation in Hyperlipidemia Treatment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ROSUVASTATIN	4	2
EZETIMIBE	4	1
ONGERICIMAB	3	3
CHEMBL1357356	0	1