metabolic syndrome X

Summary

metabolic syndrome X (MONDO:0011565) is a disease with 1 cohort gene (2 GWAS associations across 4 studies) and 194 clinical trials. Top therapeutic interventions include rosiglitazone, aripiprazole, and berberine.

At a glance

• Cohort genes: 1
• GWAS associations: 2
• ClinVar variants: 7
• Clinical trials: 194

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	metabolic syndrome X
Mondo ID	MONDO:0011565
MeSH	D024821
OMIM	605552
DOID	DOID:14221
SNOMED CT	237602007
UMLS	C4552048
MedGen	1640883
Is cancer (heuristic)	no

Also known as: abdominal obesity metabolic syndrome · abdominal obesity-metabolic syndrome 1 · AOMS1 · metabolic syndrome type X

Data availability: 7 ClinVar variants · 2 GWAS associations (4 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › abdominal obesity-metabolic syndrome › metabolic syndrome X

Related subtypes (4): abdominal obesity-metabolic syndrome quantitative trait locus 2, abdominal obesity-metabolic syndrome 3, LIPE-related familial partial lipodystrophy, abdominal obesity-metabolic syndrome 4

Genetics & variants

GWAS landscape

2 GWAS associations across 4 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1023489659	1e-12	CUX1	G	3.9
rs530245205	4e-12	RPSAP1 - NFATC2	T	1.76

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477434	Verma A	2024	3,950	443,687	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477433	Verma A	2024	1,119	119,783	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479950	Verma A	2024	1,119	119,783	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477432	Verma A	2024	553	58,764	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	0
low_freq (0.01-0.05)	0
rare (<0.01)	2
unknown	0

Functional consequences

Consequence	Count
intron_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1023489659	7	101997684	G>A	0	intron_variant	CUX1	1e-12	Tier 4: intronic/intergenic
rs530245205	20	51259544	T>C	0	intron_variant	RPSAP1 - NFATC2	4e-12	Tier 4: intronic/intergenic

ClinVar germline variants

7 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075423	NM_001386140.1(MTTP):c.141del (p.Gly49fs)	MTTP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385779	NM_001386140.1(MTTP):c.1636_1637dup (p.Ile547fs)	MTTP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1020417	NM_001386140.1(MTTP):c.1636A>G (p.Ile546Val)	MTTP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1358938	NM_001386140.1(MTTP):c.1301C>T (p.Thr434Ile)	MTTP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1380622	NM_001386140.1(MTTP):c.863C>A (p.Pro288His)	MTTP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1381641	NM_001386140.1(MTTP):c.1385A>T (p.Glu462Val)	MTTP	Uncertain significance	criteria provided, multiple submitters, no conflicts
14242	NM_001386140.1(MTTP):c.383T>C (p.Ile128Thr)	MTTP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTTP	Orphanet:14	Abetalipoproteinemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTTP	HGNC:7467	ENSG00000138823	P55157	Microsomal triglyceride transfer protein large subunit	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTTP	Microsomal triglyceride transfer protein large subunit	Catalyzes the transport of triglyceride, cholesteryl ester, and phospholipid between phospholipid surfaces.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

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

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTTP	Other/Unknown	no		Vitellogenin_N, Lipovitellin_superhlx_dom, Vitellinogen_b-sht_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
ileum	1
jejunal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTTP	162	broad	marker	jejunal mucosa, ileal mucosa, ileum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTTP	1,437

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTTP	P55157	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
VLDL assembly	1	2284.0×	0.002	MTTP
LDL remodeling	1	1903.3×	0.002	MTTP
Chylomicron assembly	1	1142.0×	0.002	MTTP
Plasma lipoprotein assembly	1	713.8×	0.002	MTTP
Plasma lipoprotein remodeling	1	475.8×	0.003	MTTP
Plasma lipoprotein assembly, remodeling, and clearance	1	228.4×	0.005	MTTP
Transport of small molecules	1	25.1×	0.040	MTTP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
plasma lipoprotein particle assembly	1	16852.0×	9e-04	MTTP
triglyceride transport	1	4213.0×	0.001	MTTP
chylomicron assembly	1	4213.0×	0.001	MTTP
very-low-density lipoprotein particle assembly	1	1203.7×	0.002	MTTP
low-density lipoprotein particle remodeling	1	1053.2×	0.002	MTTP
lipoprotein transport	1	991.3×	0.002	MTTP
lipoprotein metabolic process	1	936.2×	0.002	MTTP
phospholipid transport	1	702.2×	0.003	MTTP
triglyceride metabolic process	1	443.5×	0.004	MTTP
response to calcium ion	1	318.0×	0.005	MTTP
protein secretion	1	263.3×	0.005	MTTP
circadian rhythm	1	244.2×	0.005	MTTP
establishment of localization in cell	1	160.5×	0.007	MTTP
cholesterol homeostasis	1	156.0×	0.007	MTTP
lipid metabolic process	1	91.6×	0.011	MTTP

Therapeutics

Drugs indicated for this disease

0 approved, 17 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Acarbose	Phase 3 (in late-stage trials)
Anakinra	Phase 3 (in late-stage trials)
Atorvastatin	Phase 3 (in late-stage trials)
Empagliflozin	Phase 3 (in late-stage trials)
Ezetimibe	Phase 3 (in late-stage trials)
Inulin	Phase 3 (in late-stage trials)
Liraglutide	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Pioglitazone	Phase 3 (in late-stage trials)
Resveratrol	Phase 3 (in late-stage trials)
Rimonabant	Phase 3 (in late-stage trials)
Rosiglitazone	Phase 3 (in late-stage trials)
Rosuvastatin	Phase 3 (in late-stage trials)
Testosterone	Phase 3 (in late-stage trials)
Titanium Dioxide	Phase 3 (in late-stage trials)
Topiramate	Phase 3 (in late-stage trials)
Valsartan	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acacia, Acipimox, Allopurinol, Anastrozole, Aspirin, Cholecalciferol, Dapagliflozin, Etanercept, Fenofibrate, Goserelin, Inositol, MK-0767, Melatonin, Metreleptin, Niacin.

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
MTTP	LOMITAPIDE MESYLATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTTP	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LOMITAPIDE MESYLATE	4	MTTP
LOMITAPIDE	4	MTTP
DIRLOTAPIDE	2	MTTP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MTTP	19	Binding:15, Functional:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
LOMITAPIDE MESYLATE	4	MTTP
LOMITAPIDE	4	MTTP
DIRLOTAPIDE	2	MTTP

Druggability pyramid

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

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

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 194.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	135
PHASE2	16
PHASE4	15
PHASE2/PHASE3	10
PHASE3	9
PHASE1/PHASE2	4
EARLY_PHASE1	3
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00224822	PHASE4	COMPLETED	The Effects of Aripiprazole on Patients With Metabolic Syndrome
NCT00225355	PHASE4	TERMINATED	Rosiglitazone Versus Placebo in Chronic Stable Angina
NCT00242814	PHASE4	COMPLETED	Phase IV, 9 Weeks Comparison Between MICARDIS 80 mg and Amlodipine 10 mg on Biological PPAR Gamma Activities
NCT00272311	PHASE4	COMPLETED	Aspirin Dose and Atherosclerosis in Patients With Metabolic Syndrome
NCT00296803	PHASE4	COMPLETED	PROCLAIM: Study Examining Effects of Clopidogrel Compared to Placebo on Inflammation in Subjects With Metabolic Syndrome
NCT00304993	PHASE4	COMPLETED	Study of Niacin and Rosiglitazone in Dysmetabolic Dyslipidemia
NCT00325936	PHASE4	COMPLETED	The Effects of Cilnidipine on Metabolic Syndrome Improvement
NCT00338949	PHASE4	COMPLETED	Ziprasidone for Improving Insulin Sensitivity in People With Schizophrenia Who Are at Risk for Diabetes
NCT00395486	PHASE4	COMPLETED	ROMEO (Rosuvastatin in Metabolic syndrOme)
NCT00515021	PHASE4	COMPLETED	Diurnal Variation of Plasminogen Activator Inhibitor-1
NCT00573950	PHASE4	UNKNOWN	Effects of Cilostazol on Plasma Adipocytokine and Arterial Stiffness
NCT00608465	PHASE4	TERMINATED	Defining Strategies for Improving Endothelial and Fibrinolytic Dysfunction in Obesity
NCT01887119	PHASE4	TERMINATED	Aldosterone Antagonism and Microvascular Function
NCT02283242	PHASE4	COMPLETED	Galantamine Effects in Patients With Metabolic Syndrome
NCT00111956	PHASE2/PHASE3	COMPLETED	Effects of Tumor Necrosis Factor (TNF)-Alpha Antagonism in Patients With Metabolic Syndrome
NCT00147264	PHASE3	COMPLETED	Telmisartan-Induced Reduction in Intra-Myocellular Lipids Trial
NCT00228176	PHASE3	TERMINATED	Atherosclerosis Underlying Development Assessed by Intima-Media Thickness in Patients on Rimonabant
NCT00243984	PHASE3	SUSPENDED	Efficacy of Topiramate for Weight Loss in Subjects With Metabolic Syndrome
NCT00399997	PHASE2/PHASE3	UNKNOWN	Evaluation of Effect of Exercise on Prescription
NCT00545805	PHASE2/PHASE3	COMPLETED	Surgical Removal of Visceral Fat Tissue (Omentectomy) Associated to Bariatric Surgery: Effects on Insulin Sensitivity
NCT00663104	PHASE3	TERMINATED	Effect of Exercise and Phytoestrogen on Bone, Metabolic Syndrome Criteria and Complaints of the Early Menopause
NCT00733772	PHASE2/PHASE3	COMPLETED	Flaxseed Intervention on Metabolic Syndrome
NCT00742742	PHASE2/PHASE3	COMPLETED	Walnut Intervention on Metabolic Syndrome (WIMS)
NCT01022411	PHASE2/PHASE3	COMPLETED	Brown Rice Intervention on Metabolic Syndrome (BRIMS)
NCT01044680	PHASE2/PHASE3	COMPLETED	Effects of NUTRIOSE®FB Dietary Fiber Supplementation on Satiety, Body Fat, and Metabolic Syndrome in Overweight Adult Men
NCT01465620	PHASE3	COMPLETED	Dietetic and Hygiene Measures in Metabolic Neuropathies: the Neurodiet Study
NCT01794429	PHASE3	COMPLETED	Treatment of Antipsychotic-associated Obesity With a GLP-1 Analogue
NCT01849068	PHASE3	COMPLETED	Effects of Selective Inhibition of Cholesterol Absorption With Ezetimibe on Intestinal Cholesterol Homeostasis in Dyslipidemic Men With Insulin-resistance - a Pilot Study
NCT01872182	PHASE3	TERMINATED	Efficacy and Safety Study of ALS-L1023 in Patients With Abdominal Obesity of Metabolic Syndrome
NCT02113241	PHASE2/PHASE3	COMPLETED	Effect of Dapagliflozin Administration on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion
NCT02407522	PHASE2/PHASE3	COMPLETED	The Improvements of Dietary Supplement of Black Rice on Metabolic Syndrome
NCT02672592	PHASE3	COMPLETED	Effects of Interleukin-1 Beta on Low Testosterone Levels in Men With Obesity and Metabolic Syndrome
NCT02983188	PHASE2/PHASE3	COMPLETED	Berberine as Adjuvant Treatment for Schizophrenia Patients
NCT00130286	PHASE1/PHASE2	COMPLETED	Growth Hormone and/or Rosiglitazone for HIV-Associated Increased Abdominal Fat and Insulin Resistance
NCT00166036	PHASE2	COMPLETED	Effect of Statins on Oxidative Stress and Endothelial Progenitor Cells
NCT00194428	PHASE1/PHASE2	COMPLETED	Weight and Metabolic Effects of an Almond Enriched Hypocaloric, Low Fat Diet on Overweight and Obese Persons
NCT00200993	PHASE2	COMPLETED	Peripheral Effects of Exercise on Cardiovascular Health (STRRIDE I)
NCT00264667	PHASE2	COMPLETED	Study In Patients With Dyslipidaemia
NCT00275145	PHASE2	COMPLETED	Effects of Resistance and Aerobic Exercise on Cardiovascular Health

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ROSIGLITAZONE	4	6
ARIPIPRAZOLE	4	3
BERBERINE	4	3
CLOPIDOGREL	4	3
EPLERENONE	4	3
FENOFIBRATE	4	2
ROSUVASTATIN	4	2
AMISULPRIDE	4	1
AMLODIPINE	4	1
ANAKINRA	4	1
ASPIRIN	4	1
ATORVASTATIN	4	1
CILOSTAZOL	4	1
FISH OIL	4	1
GALANTAMINE	4	1
NIACIN	4	1
ORLISTAT	4	1
PRAVASTATIN	4	1
RAMIPRIL	4	1
RIMONABANT	4	1
TELMISARTAN	4	1
TITANIUM DIOXIDE	4	1
TOPIRAMATE	4	1
TRIGLYCERIDES, MEDIUM-CHAIN	4	1
CORN OIL	3	2
ASTAXANTHIN	3	1
CILNIDIPINE	3	1
MALTODEXTRIN	3	1
MEDIUM-CHAIN TRIGLYCERIDES	3	1
OATMEAL, COLLOIDAL	3	1