Transient ischemic attack

Summary

Transient ischemic attack (MONDO:0005264) is a disease with 1 cohort gene (1 GWAS associations across 49 studies) and 336 clinical trials. Top therapeutic interventions include aspirin, apixaban, and colchicine.

At a glance

• Cohort genes: 1
• GWAS associations: 1
• ClinVar variants: 2
• Clinical trials: 336

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	transient ischemic attack
Mondo ID	MONDO:0005264
EFO	EFO:0003764
MeSH	D002546
DOID	DOID:224
ICD-11	826335789
NCIT	C50781
SNOMED CT	266257000
UMLS	C0007787
MedGen	853
Is cancer (heuristic)	no

Also known as: attack, transient ischaemic · attack, transient ischemic · ischaemic attack, transient · ischemic attack, transient · TIA · TIA - transient ischemic attack · transient cerebral ischemia (disorder) [ambiguous] · transient ischaemic attack (disease) · transient ischaemic attacks · transient ischemic attack · transient ischemic attack (disease) · transient ischemic attacks

Data availability: 2 ClinVar variants · 1 GWAS association (49 studies) · 1 HPO phenotype · 68 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › ischemic disease › brain ischemia › transient ischemic attack

Related subtypes (2): brain hypoxia - ischemia, pediatric arterial ischemic stroke

Subtypes (1): vertebral artery insufficiency

Genetics & variants

GWAS landscape

1 GWAS associations across 49 studies. Top hits map to 0 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs276472	1e-07	IL20RA - IL22RA2	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477996	Verma A	2024	30,878	402,820	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90476668	Verma A	2024	30,830	284,838	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90476904	Verma A	2024	29,520	286,148	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90476866	Verma A	2024	18,582	297,086	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90476995	Verma A	2024	14,887	300,781	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90476629	Verma A	2024	13,299	302,369	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479383	Verma A	2024	10,472	305,196	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90473330	UK Biobank Whole-Genome Sequencing Consortium	2025	9,846	448,594	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90476632	Verma A	2024	9,345	306,323	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477995	Verma A	2024	7,606	109,704	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	1

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs276472	6	137136105	G>T	0.05	intergenic_variant	IL20RA - IL22RA2	1e-07	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
208501	NM_000435.3(NOTCH3):c.457C>T (p.Arg153Cys)	NOTCH3	Pathogenic	criteria provided, multiple submitters, no conflicts
523370	NM_000435.3(NOTCH3):c.1450T>G (p.Cys484Gly)	NOTCH3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOTCH3	Orphanet:136	Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy
NOTCH3	Orphanet:2591	Infantile myofibromatosis
NOTCH3	Orphanet:2789	Lateral meningocele syndrome

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
NOTCH3	HGNC:7883	ENSG00000074181	Q9UM47	Neurogenic locus notch homolog protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOTCH3	Neurogenic locus notch homolog protein 3	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOTCH3	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

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
popliteal artery	1
right coronary artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOTCH3	273	ubiquitous	marker	popliteal artery, tibial artery, right coronary artery

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH3	4,403

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH3	Q9UM47	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Defective LFNG causes SCDO3	1	2284.0×	0.002	NOTCH3
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	1903.3×	0.002	NOTCH3
Noncanonical activation of NOTCH3	1	1427.5×	0.002	NOTCH3
Pre-NOTCH Processing in Golgi	1	634.4×	0.003	NOTCH3
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	475.8×	0.003	NOTCH3
NOTCH3 Intracellular Domain Regulates Transcription	1	439.2×	0.003	NOTCH3
Notch-HLH transcription pathway	1	407.9×	0.003	NOTCH3
Pre-NOTCH Transcription and Translation	1	122.8×	0.008	NOTCH3

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
glomerular capillary formation	1	5617.3×	0.002	NOTCH3
neuroblast differentiation	1	2106.5×	0.003	NOTCH3
neuron fate commitment	1	802.5×	0.004	NOTCH3
artery morphogenesis	1	674.1×	0.004	NOTCH3
forebrain development	1	351.1×	0.006	NOTCH3
positive regulation of smooth muscle cell proliferation	1	330.4×	0.006	NOTCH3
positive regulation of miRNA transcription	1	290.6×	0.006	NOTCH3
negative regulation of neuron differentiation	1	271.8×	0.006	NOTCH3
Notch signaling pathway	1	141.6×	0.009	NOTCH3
axon guidance	1	90.6×	0.013	NOTCH3
negative regulation of transcription by RNA polymerase II	1	17.7×	0.062	NOTCH3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NOTCH3

Therapeutics

Drugs indicated for this disease

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

Drug	Development status
Aspirin	Phase 3 (in late-stage trials)
Clopidogrel	Phase 3 (in late-stage trials)
Warfarin	Phase 3 (in late-stage trials)

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

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOTCH3	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH3	3	Binding:3

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

1 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)
VAREGACESTAT	2	NOTCH3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	NOTCH3
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: 336.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	263
PHASE3	26
PHASE4	14
PHASE2	14
PHASE2/PHASE3	9
PHASE1	8
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03568890	PHASE4	ACTIVE_NOT_RECRUITING	Short-Term Anticoagulation Versus Antiplatelet Therapy for Preventing Device Thrombosis Following Left Atrial Appendage Closure
NCT05780905	PHASE4	RECRUITING	Effects of Semaglutide on Intracranial Blood Flow and Brain-Barrier Permeability in Type-2 Diabetes
NCT05995600	PHASE4	RECRUITING	Comparison of Clopidogrel-based Antiplatelet Therapy Versus Warfarin As Secondary Prevention Strategy for AntiPhospholipid Syndrome-related STROKE
NCT06785727	PHASE4	NOT_YET_RECRUITING	StAtins in Frail OldEr Patients with Ischemic Stroke or Transient Ischemic Attack - the Randomized Controlled Trial
NCT00161070	PHASE4	COMPLETED	ESPRIT: European/Australasian Stroke Prevention in Reversible Ischaemia Trial
NCT00724724	PHASE4	UNKNOWN	The Effectiveness and Safety of Butylphthalide Soft Capsules in Secondary Prevention of Ischemic Stroke Trial
NCT00931788	PHASE4	COMPLETED	Preventing Recurrent Vascular Events in Patients With Stroke or Transient Ischemic Attack
NCT01097967	PHASE4	UNKNOWN	Sleep Disordered Breathing in Transient Ischemic Attack (TIA)/Ischemic Stroke and Continuous Positive Airway Pressure (CPAP) Treatment Efficacy
NCT01236508	PHASE4	TERMINATED	Relation of Carotid Artery Plaque Inflammation, Covert Stroke and White Matter Disease
NCT01563731	PHASE4	COMPLETED	Optimal Blood Pressure and Cholesterol Targets for Preventing Recurrent Stroke in Hypertensives
NCT01975194	PHASE4	TERMINATED	Rosuvastatin in African Americans With Cerebrovascular Disease
NCT02144831	PHASE4	WITHDRAWN	The Middle East Dual Anti-platelet Treatment in Acute Transient Ischemic Attack
NCT03749057	PHASE4	COMPLETED	Early Rivaroxaban for Acute Ischemic Stroke or TIA Patients With Atrial Fibrillation
NCT06522113	PHASE4	COMPLETED	Cilostazol and Aspirin in Stroke and TIA
NCT05476991	PHASE3	RECRUITING	Evaluation of Low Dose Colchicine and Ticagrelor in Prevention of Ischemic Stroke in Patients With Stroke Due to Atherosclerosis
NCT06225752	PHASE3	RECRUITING	Probucol for Symptomatic Intracranial and Extracranial Artery Stenosis
NCT06319846	PHASE3	RECRUITING	Tirofiban for Patients With intraCranial Artery Stenosis and High-risk Acute Non-disabling Cerebrovascular Events(CHANCE-4）
NCT06615726	PHASE3	ACTIVE_NOT_RECRUITING	Regular Physical Exercise in Patients With Symptomatic Intracranial Arterial Stenosis
NCT06653348	PHASE2/PHASE3	RECRUITING	Ticagrelor Based De-Escalation of Dual Antiplatelet Therapy in Ischemic Stroke
NCT07174414	PHASE3	NOT_YET_RECRUITING	Cilostazol for Prevention of Recurrent Stroke Trial
NCT00029146	PHASE3	TERMINATED	Carotid Occlusion Surgery Study
NCT00061022	PHASE3	COMPLETED	Safety and Effectiveness of NXY-059 for the Treatment of Patients Who Have Suffered From a Stroke
NCT00109382	PHASE2/PHASE3	COMPLETED	Fast Assessment of Stroke and Transient Ischemic Attack to Prevent Early Recurrence (FASTER)
NCT00119626	PHASE3	COMPLETED	Safety and Effectiveness of NXY-059 for the Treatment of Patients Who Have Suffered From a Stroke
NCT00190398	PHASE3	COMPLETED	EVA3S: Endarterectomy Versus Angioplasty in Patients With Severe Symptomatic Carotid Stenosis
NCT00201461	PHASE2/PHASE3	UNKNOWN	Evaluation of the STARFlex® Septal Closure System in Patients With a Stroke or TIA Due to the Possible Passage of a Clot of Unknown Origin Through a Patent Foramen Ovale (PFO)
NCT00235248	PHASE3	COMPLETED	Aortic Arch Related Cerebral Hazard Trial (ARCH)
NCT00514800	PHASE3	COMPLETED	Home Blood Pressure Monitoring Trial
NCT00536562	PHASE3	COMPLETED	Cardiac Rehabilitation for TIA Patients
NCT00600327	PHASE3	COMPLETED	Carotid Artery Revascularization Using the Boston Scientific EPI Filter Wire EZ™ and the EndoTex™ NexStent™
NCT00662818	PHASE3	COMPLETED	Telcagepant (MK-0974) Treatment of Migraine in Participants With Stable Vascular Disease (MK-0974-034)
NCT00816166	PHASE2/PHASE3	TERMINATED	VISSIT Intracranial Stent Study for Ischemic Therapy
NCT00979589	PHASE3	COMPLETED	Clopidogrel in High-risk Patients With Acute Non-disabling Cerebrovascular Events
NCT00984308	PHASE2/PHASE3	COMPLETED	Diagnosis and Treatment of Sleep Apnea in Cerebrovascular Disease
NCT00991029	PHASE3	TERMINATED	Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial
NCT01923818	PHASE2/PHASE3	UNKNOWN	Treatment of Rivaroxaban Versus Aspirin for Non-disabling Cerebrovascular Events
NCT01924325	PHASE2/PHASE3	UNKNOWN	Apixaban Versus Dual-antiplatelet Therapy (Clopidogrel and Aspirin) in Acute Non-disabling Cerebrovascular Events
NCT01994720	PHASE3	COMPLETED	[SOCRATES -Acute Stroke Or Transient IsChaemic Attack TReated With Aspirin or Ticagrelor and Patient OutcomES]
NCT02283294	PHASE3	COMPLETED	Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation
NCT02506140	PHASE2/PHASE3	COMPLETED	Platelet Reactivity in Acute Non-disabling Cerebrovascular Events

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ASPIRIN	4	14
APIXABAN	4	3
COLCHICINE	4	3
RIVAROXABAN	4	3
CILOSTAZOL	4	2
DABIGATRAN ETEXILATE	4	2
ROSUVASTATIN	4	2
WARFARIN	4	2
ALTEPLASE	4	1
BEMPEDOIC ACID	4	1
CYANOCOBALAMIN	4	1
DIPYRIDAMOLE	4	1
FLUVASTATIN	4	1
MINOCYCLINE HYDROCHLORIDE	4	1
PEMAFIBRATE	4	1
PRAVASTATIN	4	1
PROBUCOL	4	1
PYRIDOXINE	4	1
SEMAGLUTIDE	4	1
TIROFIBAN	4	1
DABIGATRAN	3	3
DISUFENTON SODIUM	3	2
RAC-3-N-BUTYLPHTHALIDE	3	2
FERROUS SUCCINATE	3	1
LEVOSIMENDAN	3	1
LYCOPENE	3	1
MILVEXIAN	3	1
TELCAGEPANT	3	1
LUFENURON	2	1
REFANEZUMAB	2	1