Peripheral arterial disease

Summary

Peripheral arterial disease (MONDO:0005386) is a disease with 40 cohort genes (271 GWAS associations across 40 studies) and 847 clinical trials. Top therapeutic interventions include clopidogrel, aspirin, and cilostazol.

At a glance

• Cohort genes: 40
• GWAS associations: 271
• Clinical trials: 847

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peripheral arterial disease
Mondo ID	MONDO:0005386
EFO	EFO:0004265
MeSH	D058729
DOID	DOID:0050830
ICD-11	1821859817
NCIT	C84496
SNOMED CT	399957001
UMLS	C1704436
MedGen	352846
Is cancer (heuristic)	no

Also known as: PAD · pad · peripheral arterial disorder

Data availability: 271 GWAS associations (40 studies).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › vascular disorder › arterial disorder › peripheral arterial disease

Related subtypes (29): vertebral artery insufficiency, splenic artery aneurysm, basilar artery insufficiency, arteriosclerosis disorder, subclavian artery aneurysm, pulmonary artery choriocarcinoma, pulmonary artery leiomyosarcoma, coronary artery disorder, hypertensive disorder, carotid artery disorder, pulmonary embolism, hypotensive disorder, large artery stroke, aortic disorder, cervical artery dissection, anterior spinal artery syndrome, fibromuscular dysplasia, retinal arterial tortuosity, Sneddon syndrome, celiac trunk compression syndrome, pediatric arterial ischemic stroke, absence of the pulmonary artery, arterial occlusion, aberrant subclavian artery, anterior spinal artery stroke, arteritis, pulmonary artery disease, fibromuscular dysplasia, multifocal, carotid web

Subtypes (1): peripheral ischemia

Genetics & variants

GWAS landscape

271 GWAS associations across 40 studies. Top hits map to 27 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs118039278	7e-50	LPA	A	1.26
rs1537372	7e-41	CDKN2B-AS1	T	1.12
rs10851907	1e-35	CHRNA3 - CHRNB4	A	1.06
rs1975514	2e-23	COL4A1	C	1.05
rs10757271	2e-22	CDKN2B-AS1	G	0.15
rs9584669	7e-14	PSMA6P4 - RPL7AP61	C	1.72
rs10757272	1e-13	CDKN2B-AS1	T	1.15
rs10455872	4e-13	LPA	G	0.28
rs6025	7e-13	F5	T	1.2
rs62084752	9e-13	KPNA2 - FBXO36P1	C	1.07
rs7528419	2e-12	CELSR2	A	1.06
rs11066301	3e-12	PTPN11	G	1.06
rs3130968	3e-12	RNU6-1133P - C6orf15	T	1.07
rs57301765	8e-12	HDAC9 - TWIST1	A	0.11
rs2107595	2e-11	HDAC9 - TWIST1	A	1.08
rs9845140	2e-11	SATB1-AS1	C
rs9526214	3e-11	LRCH1	T
rs7903146	4e-11	TCF7L2	T	1.06
rs4722172	4e-11	IL6 - MTCYBP42	G	1.08
rs948386	4e-11	ATP7BP1	G
rs505922	7e-11	ABO	C	1.06
rs13389599	8e-11	LRRTM4	?	22.26
rs138294113	1e-10	SMARCA4 - LDLR	C	1.09
rs55784307	1e-10	SMOC1 - SLC8A3	A	1.06
rs9567406	2e-10	LINC02938	G	68.32
rs1531817	3e-10	PCSK6	C
rs10757269	4e-10	CDKN2B-AS1	G	1.13
rs931794	4e-10	HYKK	G	1.14
rs9299525	6e-10	SAMD8	G
rs1364063	7e-10	CYB5B - NFAT5	T

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90103988	Bellomo TR	2022	24,009	575,511	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103989	Bellomo TR	2022	24,009	575,511	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103990	Bellomo TR	2022	24,009	575,511	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103991	Bellomo TR	2022	24,009	575,511	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103992	Bellomo TR	2022	24,009	575,511	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103993	Bellomo TR	2022	24,009	575,511	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103994	Bellomo TR	2022	24,009	575,511	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103995	Bellomo TR	2022	24,009	575,511	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103996	Bellomo TR	2022	24,009	150,983	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
GCST90103997	Bellomo TR	2022	24,009	150,983	Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	3
Tier 3: regulatory	5
Tier 4: intronic/intergenic	41

MAF distribution

Bucket	Variants
common (>=0.05)	47
low_freq (0.01-0.05)	3
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	29
intergenic_variant	10
regulatory_region_variant	5
3_prime_UTR_variant	3
non_coding_transcript_exon_variant	2
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs118039278	6	160564494	G>A	0.07	intron_variant	LPA	7e-50	Tier 4: intronic/intergenic
rs1537372	9	22103184	G>A,T	0.42	intron_variant	CDKN2B-AS1	7e-41	Tier 4: intronic/intergenic
rs10851907	15	78623522	G>A,C	0.41	intron_variant	CHRNA3 - CHRNB4	1e-35	Tier 4: intronic/intergenic
rs1975514	13	110176544	T>C,G	0.36	intron_variant	COL4A1	2e-23	Tier 4: intronic/intergenic
rs10757271	9	22076796	A>C,G,T	0.05	intron_variant	CDKN2B-AS1	2e-22	Tier 4: intronic/intergenic
rs9584669	13	97711228	T>C	0.05	intergenic_variant	PSMA6P4 - RPL7AP61	7e-14	Tier 4: intronic/intergenic
rs10757272	9	22088261	C>T	0.46	intron_variant	CDKN2B-AS1	1e-13	Tier 4: intronic/intergenic
rs10455872	6	160589086	A>G	0.05	intron_variant	LPA	4e-13	Tier 4: intronic/intergenic
rs6025	1	169549811	C>A,G,T	0.03	missense_variant	F5	7e-13	Tier 1: coding
rs62084752	17	68093252	C>A,G,T	0.25	intergenic_variant	KPNA2 - FBXO36P1	9e-13	Tier 4: intronic/intergenic
rs7528419	1	109274570	A>G	0.22	3_prime_UTR_variant	CELSR2	2e-12	Tier 2: splice/UTR
rs11066301	12	112433568	A>G	0.43	intron_variant	PTPN11	3e-12	Tier 4: intronic/intergenic
rs3130968	6	31097294	C>G,T	0.19	intergenic_variant	RNU6-1133P - C6orf15	3e-12	Tier 4: intronic/intergenic
rs57301765	7	19013110	G>A	0.05	intergenic_variant	HDAC9 - TWIST1	8e-12	Tier 4: intronic/intergenic
rs2107595	7	19009765	G>A,C,T	0.187	regulatory_region_variant	HDAC9 - TWIST1	2e-11	Tier 3: regulatory
rs9845140	3	18687386	C>A,T	0.27	intron_variant	SATB1-AS1	2e-11	Tier 4: intronic/intergenic
rs9526214	13	46663078	T>A,C,G	0.24	intron_variant	LRCH1	3e-11	Tier 4: intronic/intergenic
rs7903146	10	112998590	C>G,T	0.294	intron_variant	TCF7L2	4e-11	Tier 4: intronic/intergenic
rs4722172	7	22746913	G>A	0.196	intergenic_variant	IL6 - MTCYBP42	4e-11	Tier 4: intronic/intergenic
rs948386	18	22418847	G>A,C	0.42	non_coding_transcript_exon_variant	ATP7BP1	4e-11	Tier 4: intronic/intergenic
rs505922	9	133273813	C>T	0.337	intron_variant	ABO	7e-11	Tier 4: intronic/intergenic
rs13389599	2	76861472	T>C	0.05	intron_variant	LRRTM4	8e-11	Tier 4: intronic/intergenic
rs138294113	19	11081053	C>T	0.121	intergenic_variant	SMARCA4 - LDLR	1e-10	Tier 4: intronic/intergenic
rs55784307	14	70034647	C>A,G	0.19	intergenic_variant	SMOC1 - SLC8A3	1e-10	Tier 4: intronic/intergenic
rs9567406	13	44303182	A>G,T	0.11	intron_variant	LINC02938	2e-10	Tier 4: intronic/intergenic
rs1531817	15	101366532	C>A	0.32	intron_variant	PCSK6	3e-10	Tier 4: intronic/intergenic
rs10757269	9	22072265	A>C,G,T	0.47	intron_variant	CDKN2B-AS1	4e-10	Tier 4: intronic/intergenic
rs931794	15	78533838	G>A,C	0.34	3_prime_UTR_variant	HYKK	4e-10	Tier 2: splice/UTR
rs9299525	10	75118267	G>A,C	0.42	intron_variant	SAMD8	6e-10	Tier 4: intronic/intergenic
rs1364063	16	69554669	T>C	0.41	intergenic_variant	CYB5B - NFAT5	7e-10	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 47 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

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

Gene	HGNC	Evidence routes
HLA-B	HLA-B	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
TCF7L2	Orphanet:528084	Non-specific syndromic intellectual disability
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus
MACF1	Orphanet:572013	Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome
COG6	Orphanet:363523	Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome
COG6	Orphanet:464443	COG6-CGD
CREB3L1	Orphanet:216812	Osteogenesis imperfecta type 3
CREB3L1	Orphanet:79105	Myxofibrosarcoma
SMOC1	Orphanet:1106	Microphthalmia with limb anomalies
COL4A1	Orphanet:36383	COL4A1/2-related familial vascular leukoencephalopathy
COL4A1	Orphanet:477749	Pontine autosomal dominant microangiopathy with leukoencephalopathy
COL4A1	Orphanet:481986	Familial schizencephaly
COL4A1	Orphanet:73229	HANAC syndrome
COL4A1	Orphanet:75326	Familial isolated retinal arteriolar tortuosity
COL4A1	Orphanet:899	Walker-Warburg syndrome
COL4A1	Orphanet:99810	Familial porencephaly
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
EDNRA	Orphanet:443995	Mandibulofacial dysostosis with alopecia
EDNRA	Orphanet:586	Cystic fibrosis
F5	Orphanet:131	Budd-Chiari syndrome
F5	Orphanet:326	Congenital factor V deficiency
F5	Orphanet:329217	Cerebral sinovenous thrombosis
F5	Orphanet:391320	East Texas bleeding disorder
F5	Orphanet:599579	Factor V Amsterdam bleeding disorder
F5	Orphanet:600194	Factor V Atlanta bleeding disorder
HABP2	Orphanet:319487	Familial papillary or follicular thyroid carcinoma
HLA-B	Orphanet:117	Behçet disease
HLA-B	Orphanet:275798	Pulmonary arterial hypertension associated with connective tissue disease
HLA-B	Orphanet:29207	Reactive arthritis
HLA-B	Orphanet:3287	Takayasu arteritis
HLA-B	Orphanet:36426	Stevens-Johnson syndrome
HLA-B	Orphanet:397	Giant cell arteritis
IGLL1	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
IL6	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis
LDLR	Orphanet:391665	Homozygous familial hypercholesterolemia
LPL	Orphanet:309015	Familial lipoprotein lipase deficiency
MAPK10	Orphanet:2382	Lennox-Gastaut syndrome
PTDSS1	Orphanet:2658	Lenz-Majewski hyperostotic dysplasia
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

40 cohort genes, 39 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	40

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CNNM1	HGNC:102	ENSG00000119946	Q9NRU3	Metal transporter CNNM1	gwas
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
SORT1	HGNC:11186	ENSG00000134243	Q99523	Sortilin	gwas
TCF7L2	HGNC:11641	ENSG00000148737	Q9NQB0	Transcription factor 7-like 2	gwas
UTRN	HGNC:12635	ENSG00000152818	P46939	Utrophin	gwas
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	gwas
MACF1	HGNC:13664	ENSG00000127603	O94854	Microtubule-actin cross-linking factor 1, isoforms 6/7	gwas
HDAC9	HGNC:14065	ENSG00000048052	Q9UKV0	Histone deacetylase 9	gwas
SYTL3	HGNC:15587	ENSG00000164674	Q4VX76	Synaptotagmin-like protein 3	gwas
OSBPL10	HGNC:16395	ENSG00000144645	Q9BXB5	Oxysterol-binding protein-related protein 10	gwas
COG6	HGNC:18621	ENSG00000133103	Q9Y2V7	Conserved oligomeric Golgi complex subunit 6	gwas
CREB3L1	HGNC:18856	ENSG00000157613	Q96BA8	Cyclic AMP-responsive element-binding protein 3-like protein 1	gwas
CSMD3	HGNC:19291	ENSG00000164796	Q7Z407	CUB and sushi domain-containing protein 3	gwas
CHRNA3	HGNC:1957	ENSG00000080644	P32297	Neuronal acetylcholine receptor subunit alpha-3	gwas
SMOC1	HGNC:20318	ENSG00000198732	Q9H4F8	SPARC-related modular calcium-binding protein 1	gwas
MTHFD1L	HGNC:21055	ENSG00000120254	Q6UB35	Monofunctional C1-tetrahydrofolate synthase, mitochondrial	gwas
BMP8A	HGNC:21650	ENSG00000183682	Q7Z5Y6	Bone morphogenetic protein 8A	gwas
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	gwas
NUTM2F	HGNC:23450	ENSG00000130950	A1L443	NUT family member 2F	gwas
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gwas
NSMCE1	HGNC:29897	ENSG00000169189	Q8WV22	Non-structural maintenance of chromosomes element 1 homolog	gwas
RGL1	HGNC:30281	ENSG00000143344	Q9NZL6	Ral guanine nucleotide dissociation stimulator-like 1	gwas
EDNRA	HGNC:3179	ENSG00000151617	P25101	Endothelin-1 receptor	gwas
CELSR2	HGNC:3231	ENSG00000143126	Q9HCU4	Cadherin EGF LAG seven-pass G-type receptor 2	gwas
CDKN2B-AS1	HGNC:34341	ENSG00000240498		CDKN2B and CDKN2A antisense cis and trans regulatory RNA 1	gwas
F5	HGNC:3542	ENSG00000198734	P12259	Coagulation factor V	gwas
HABP2	HGNC:4798	ENSG00000148702	Q14520	Factor VII-activating protease	gwas
HLA-B	HGNC:4932	ENSG00000234745	P01889	HLA class I histocompatibility antigen, B alpha chain	gwas
IGLL1	HGNC:5870	ENSG00000128322	P15814	Immunoglobulin lambda-like polypeptide 1	gwas
IL6	HGNC:6018	ENSG00000136244	P05231	Interleukin-6	gwas
IPO5	HGNC:6402	ENSG00000065150	O00410	Importin-5	gwas
LDLR	HGNC:6547	ENSG00000130164	P01130	Low-density lipoprotein receptor	gwas
LPA	HGNC:6667	ENSG00000198670	P08519	Apolipoprotein(a)	gwas
LPL	HGNC:6677	ENSG00000175445	P06858	Lipoprotein lipase	gwas
MAPK10	HGNC:6872	ENSG00000109339	P53779	Mitogen-activated protein kinase 10	gwas
MMP3	HGNC:7173	ENSG00000149968	P08254	Stromelysin-1	gwas
ABO	HGNC:79	ENSG00000175164	P16442	Histo-blood group ABO system transferase	gwas
PTDSS1	HGNC:9587	ENSG00000156471	P48651	Phosphatidylserine synthase 1	gwas
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	gwas
RAP2A	HGNC:9861	ENSG00000125249	P10114	Ras-related protein Rap-2a	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CNNM1	Metal transporter CNNM1	Probable metal transporter.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
SORT1	Sortilin	Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface.
TCF7L2	Transcription factor 7-like 2	Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner.
UTRN	Utrophin	May play a role in anchoring the cytoskeleton to the plasma membrane.
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
HDAC9	Histone deacetylase 9	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
SYTL3	Synaptotagmin-like protein 3	May act as Rab effector protein and play a role in vesicle trafficking.
OSBPL10	Oxysterol-binding protein-related protein 10	Probable lipid transporter involved in lipid countertransport between the endoplasmic reticulum and the plasma membrane.
COG6	Conserved oligomeric Golgi complex subunit 6	Required for normal Golgi function.
CREB3L1	Cyclic AMP-responsive element-binding protein 3-like protein 1	Precursor of the transcription factor form (Processed cyclic AMP-responsive element-binding protein 3-like protein 1), which is embedded in the endoplasmic reticulum membrane with N-terminal DNA-binding and transcription activation domains…
CSMD3	CUB and sushi domain-containing protein 3	Involved in dendrite development.
CHRNA3	Neuronal acetylcholine receptor subunit alpha-3	Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection…
SMOC1	SPARC-related modular calcium-binding protein 1	Plays essential roles in both eye and limb development.
MTHFD1L	Monofunctional C1-tetrahydrofolate synthase, mitochondrial	May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism complementing thus the enzymatic activities of MTHFD2.
BMP8A	Bone morphogenetic protein 8A	Induces cartilage and bone formation.
COL4A1	Collagen alpha-1(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
NSMCE1	Non-structural maintenance of chromosomes element 1 homolog	RING-type zinc finger-containing E3 ubiquitin ligase that assembles with melanoma antigen protein (MAGE) to catalyze the direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to a specific substrate.
RGL1	Ral guanine nucleotide dissociation stimulator-like 1	Probable guanine nucleotide exchange factor.
EDNRA	Endothelin-1 receptor	Receptor for endothelin-1.
CELSR2	Cadherin EGF LAG seven-pass G-type receptor 2	Receptor that may have an important role in cell/cell signaling during nervous system formation.
F5	Coagulation factor V	Central regulator of hemostasis.
HABP2	Factor VII-activating protease	Cleaves the alpha-chain at multiple sites and the beta-chain between ‘Lys-53’ and ‘Lys-54’ but not the gamma-chain of fibrinogen and therefore does not initiate the formation of the fibrin clot and does not cause the fibrinolysis directly.
HLA-B	HLA class I histocompatibility antigen, B alpha chain	Antigen-presenting major histocompatibility complex class I (MHCI) molecule.
IGLL1	Immunoglobulin lambda-like polypeptide 1	Critical for B-cell development.
IL6	Interleukin-6	Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism.
IPO5	Importin-5	Functions in nuclear protein import as nuclear transport receptor.
LDLR	Low-density lipoprotein receptor	Binds low density lipoprotein /LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis.
LPA	Apolipoprotein(a)	Apo(a) is the main constituent of lipoprotein(a) (Lp(a)).
LPL	Lipoprotein lipase	Key enzyme in triglyceride metabolism.
MAPK10	Mitogen-activated protein kinase 10	Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death.
MMP3	Stromelysin-1	Metalloproteinase with a rather broad substrate specificity that can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans.
ABO	Histo-blood group ABO system transferase	This protein is the basis of the ABO blood group system.
PTDSS1	Phosphatidylserine synthase 1	Catalyzes a base-exchange reaction in which the polar head group of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) is replaced by L-serine.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.
RAP2A	Ras-related protein Rap-2a	Small GTP-binding protein which cycles between a GDP-bound inactive and a GTP-bound active form.

Protein-family classification

Druggable: 15 · Difficult: 8 · Unknown: 17 · Druggable fraction: 0.38

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
Complement	1	6.7×	0.463
Protease	3	2.8×	0.463
Scaffold/PPI	5	2.2×	0.463
Enzyme (other)	5	1.5×	0.596
Phosphatase	1	2.1×	0.667
Antibody/Immunoglobulin	2	1.5×	0.667
GPCR	2	1.2×	0.718
Kinase	1	0.7×	0.963
Other/Unknown	17	0.8×	0.968
Transcription factor	3	0.6×	0.968

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CNNM1	Other/Unknown	no		CBS_dom, CNNM, Ion_transp-like_CBS
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
SORT1	Scaffold/PPI	no		VPS10, WD40/YVTN_repeat-like_dom_sf, Sortilin_C
TCF7L2	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF
UTRN	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
MACF1	Scaffold/PPI	no		Spectrin_repeat, EF_hand_dom, GAR_dom
HDAC9	Enzyme (other)	yes	3.5.1.98	HDACs, Ureohydrolase_dom_sf, His_deacetylse_dom
SYTL3	Transcription factor	no		C2_dom, Rab_BD, Znf_FYVE_PHD
OSBPL10	Scaffold/PPI	no		Oxysterol-bd, PH_domain, PH-like_dom_sf
COG6	Other/Unknown	no		COG6, COG6_N, COG6_C
CREB3L1	Other/Unknown	no		bZIP, bZIP_sf
CSMD3	Complement	yes		Sushi_SCR_CCP_dom, CUB_dom, Sperma_CUB_dom_sf
CHRNA3	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
SMOC1	Other/Unknown	no		Thyroglobulin_1, Kazal_dom, EF-hand-dom_pair
MTHFD1L	Enzyme (other)	yes	6.3.4.3	Formate_THF_ligase, THF_DH/CycHdrlase, Formate_THF_ligase_CS
BMP8A	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
NUTM2F	Other/Unknown	no		NUT_N, NUT
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
NSMCE1	Transcription factor	no		Znf_RING, PKC_DAG/PE, Nse1
RGL1	Other/Unknown	no		RA_dom, Ras-like_Gua-exchang_fac_N, RASGEF_cat_dom
EDNRA	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETA_rcpt
CELSR2	GPCR	yes		EGF-type_Asp/Asn_hydroxyl_site, GPS, EGF
CDKN2B-AS1	Other/Unknown	no
F5	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf
HABP2	Protease	yes	3.4.21.B1	Kringle, EGF, Trypsin_dom
HLA-B	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig/MHC_CS, Ig_C1-set
IGLL1	Antibody/Immunoglobulin	yes		Ig/MHC_CS, Ig_C1-set, Ig-like_dom
IL6	Other/Unknown	no		IL-6-like, 4_helix_cytokine-like_core, IL6/GCSF/MGF_CS
IPO5	Other/Unknown	no		HEAT, Importin-beta_N, ARM-like
LDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
LPA	Protease	yes		Kringle, Trypsin_dom, Peptidase_S1A
LPL	Enzyme (other)	yes	3.1.1.34	TAG_lipase, PLAT/LH2_dom, Lipo_Lipase
MAPK10	Kinase	yes	2.7.11.24	Prot_kinase_dom, MAP_kinase_CS, Ser/Thr_kinase_AS
MMP3	Protease	yes	3.4.24.17	Hemopexin-like_dom, Pept_M10_metallopeptidase, Peptidoglycan-bd-like
ABO	Enzyme (other)	yes	2.4.1.37	Glyco_trans_6, Nucleotide-diphossugar_trans
PTDSS1	Enzyme (other)	yes	2.7.8.29	PSS
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2
RAP2A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

Expression context

Cohort genes with no expression data: 0.

38 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)	1
broad (>20)	39
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	4
right lobe of liver	4
buccal mucosa cell	3
calcaneal tendon	3
oocyte	3
right testis	3
left testis	3
liver	3
adrenal tissue	3
prefrontal cortex	2
olfactory bulb	2
inferior vagus X ganglion	2
endothelial cell	2
pancreatic ductal cell	2
dorsal motor nucleus of vagus nerve	2
monocyte	2
stromal cell of endometrium	2
Brodmann (1909) area 23	2
male germ line stem cell (sensu Vertebrata) in testis	2
ganglionic eminence	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CNNM1	176	broad	marker	postcentral gyrus, prefrontal cortex, parietal lobe
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
SORT1	291	ubiquitous	marker	inferior vagus X ganglion, corpus epididymis, subthalamic nucleus
TCF7L2	291	ubiquitous	marker	lateral nuclear group of thalamus, endothelial cell, pancreatic ductal cell
UTRN	272	ubiquitous	marker	calcaneal tendon, tendon, sural nerve
WWOX	286	ubiquitous	marker	parotid gland, cervix squamous epithelium, cranial nerve II
MACF1	303	ubiquitous	marker	inferior olivary complex, dorsal motor nucleus of vagus nerve, right lung
HDAC9	277	ubiquitous	marker	oocyte, monocyte, secondary oocyte
SYTL3	196	broad	marker	secondary oocyte, oocyte, bronchial epithelial cell
OSBPL10	264	ubiquitous	marker	secondary oocyte, oocyte, right testis
COG6	254	ubiquitous	marker	secondary oocyte, tibia, calcaneal tendon
CREB3L1	231	ubiquitous	marker	nasal cavity epithelium, stromal cell of endometrium, ileal mucosa
CSMD3	129	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, male germ line stem cell (sensu Vertebrata) in testis
CHRNA3	179	broad	marker	pigmented layer of retina, thymus, primordial germ cell in gonad
SMOC1	203	broad	marker	ganglionic eminence, inferior vagus X ganglion, right lobe of liver
MTHFD1L	236	ubiquitous	yes	right coronary artery, stromal cell of endometrium, left coronary artery
BMP8A	166	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
COL4A1	283	ubiquitous	marker	visceral pleura, placenta, right coronary artery
NUTM2F	13		yes	left testis, testis, right testis
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
NSMCE1	254	ubiquitous	marker	right testis, left testis, kidney epithelium
RGL1	291	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, dorsal root ganglion
EDNRA	253	ubiquitous	marker	cauda epididymis, seminal vesicle, visceral pleura
CELSR2	248	ubiquitous	marker	ganglionic eminence, ventricular zone, right frontal lobe
CDKN2B-AS1	169	ubiquitous	marker	mucosa of transverse colon, rectum, transverse colon
F5	206	broad	marker	right lobe of liver, liver, choroid plexus epithelium
HABP2	115	tissue_specific	marker	right lobe of liver, pancreatic ductal cell, liver
HLA-B	134	ubiquitous	marker	blood, spleen, granulocyte
IGLL1	112	tissue_specific	marker	bone marrow, bone marrow cell, male germ line stem cell (sensu Vertebrata) in testis
IL6	200	ubiquitous	marker	cartilage tissue, vena cava, gall bladder

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL6	9,239
PTPN11	6,009
WWOX	5,892
HABP2	4,008
TCF7L2	3,775
IPO5	3,552
ATXN2	3,360
HLA-B	3,209
MMP3	3,148
HDAC9	3,047

Intra-cohort edges

A	B	Sources
ATXN2	SH2B3	string_interaction
CELSR2	SORT1	string_interaction
CHRNA3	CNNM1	biogrid_interaction, intact
IL6	SORT1	intact
LPL	SORT1	intact
RAP2A	RGL1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 26 · AlphaFold-only: 13 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HLA-B	P01889	237
ABO	P16442	151
PTPN11	Q06124	115
MAPK10	P53779	65
MMP3	P08254	44
LDLR	P01130	36
F5	P12259	18
SORT1	Q99523	17
IL6	P05231	17
LPA	P08519	16
NSMCE1	Q8WV22	6
PTDSS1	P48651	6
CHRNA3	P32297	5
EDNRA	P25101	5
LPL	P06858	5
COL4A1	P02462	4
TCF7L2	Q9NQB0	3
UTRN	P46939	3
MACF1	O94854	3
IGLL1	P15814	3
IPO5	O00410	3
RAP2A	P10114	3
HDAC9	Q9UKV0	2
RGL1	Q9NZL6	2
ATXN2	Q99700	1
WWOX	Q9NZC7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTHFD1L	Q6UB35	87.45
COG6	Q9Y2V7	86.62
HABP2	Q14520	77.58
BMP8A	Q7Z5Y6	76.87
OSBPL10	Q9BXB5	75.03
SMOC1	Q9H4F8	73.69
SYTL3	Q4VX76	71.86
CNNM1	Q9NRU3	67.07
SH2B3	Q9UQQ2	63.45
CREB3L1	Q96BA8	55.66
NUTM2F	A1L443	52.27
CSMD3	Q7Z407
CELSR2	Q9HCU4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 234. Enrichment computed across 40 evidence-associated genes (27 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 27 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MAPK1 (ERK2) activation	2	84.6×	0.020	IL6, PTPN11
MAPK3 (ERK1) activation	2	76.9×	0.020	IL6, PTPN11
Interleukin-6 signaling	2	70.5×	0.020	IL6, PTPN11
Plasma lipoprotein assembly, remodeling, and clearance	3	25.4×	0.020	LDLR, LPA, LPL
Plasma lipoprotein remodeling	2	35.2×	0.060	LPA, LPL
Metabolism of vitamins and cofactors	3	12.9×	0.060	MTHFD1L, LDLR, LPL
Metabolism of fat-soluble vitamins	2	28.2×	0.075	LDLR, LPL
FLT3 Signaling	2	25.6×	0.079	SH2B3, PTPN11
Synthesis of PS	1	211.5×	0.087	PTDSS1
vRNP Assembly	1	211.5×	0.087	IPO5
Transcriptional Regulation by VENTX	2	19.7×	0.087	TCF7L2, IL6
Visual phototransduction	2	19.2×	0.087	LDLR, LPL
Signaling by SCF-KIT	2	18.4×	0.087	SH2B3, PTPN11
Retinoid metabolism and transport	2	18.4×	0.087	LDLR, LPL
Defective cleavage of FV variant at a.a.534	1	141.0×	0.103	F5
Defective cleavage of FV variant at R334	1	141.0×	0.103	F5
Assembly of collagen fibrils and other multimeric structures	2	14.8×	0.109	COL4A1, MMP3
Signaling by TCF7L2 mutants	1	105.7×	0.123	TCF7L2
MET activates PTPN11	1	84.6×	0.125	PTPN11
Chylomicron clearance	1	84.6×	0.125	LDLR
Co-inhibition by BTLA	1	84.6×	0.125	PTPN11
Collagen degradation	2	13.0×	0.125	COL4A1, MMP3
LDL remodeling	1	70.5×	0.132	LPA
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	1	60.4×	0.132	CHRNA3
STAT5 Activation	1	60.4×	0.132	PTPN11
Netrin mediated repulsion signals	1	47.0×	0.132	PTPN11
Highly calcium permeable nicotinic acetylcholine receptors	1	47.0×	0.132	CHRNA3
CREB3 factors activate genes	1	47.0×	0.132	CREB3L1
EGFR Transactivation by Gastrin	1	42.3×	0.132	MMP3
Binding of TCF/LEF:CTNNB1 to target gene promoters	1	42.3×	0.132	TCF7L2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 38 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to acetylcholine	2	110.9×	0.054	CHRNA3, EDNRA
regulation of neuroinflammatory response	2	73.9×	0.054	IL6, MMP3
cellular response to amino acid stimulus	3	24.2×	0.054	COL4A1, IPO5, MMP3
regulation of acetylcholine secretion, neurotransmission	1	443.5×	0.063	CHRNA3
regulation of striated muscle cell differentiation	1	443.5×	0.063	HDAC9
negative regulation of cortisol secretion	1	443.5×	0.063	PTPN11
negative regulation of growth hormone secretion	1	443.5×	0.063	PTPN11
regulation of protein localization to cell leading edge	1	443.5×	0.063	EDNRA
10-formyltetrahydrofolate biosynthetic process	1	221.7×	0.063	MTHFD1L
regulation of phosphatidylcholine catabolic process	1	221.7×	0.063	LDLR
formate metabolic process	1	221.7×	0.063	MTHFD1L
microvillus organization	1	221.7×	0.063	PTPN11
cellular response to human chorionic gonadotropin stimulus	1	221.7×	0.063	EDNRA
intestinal epithelial cell migration	1	221.7×	0.063	PTPN11
regulation of astrocyte activation	1	221.7×	0.063	IL6
glucagon secretion	1	221.7×	0.063	IL6
extracellular matrix constituent secretion	1	221.7×	0.063	CREB3L1
receptor-mediated endocytosis involved in cholesterol transport	1	221.7×	0.063	LDLR
negative regulation of Kit signaling pathway	1	221.7×	0.063	SH2B3
podocyte apoptotic process	1	221.7×	0.063	EDNRA
neutrophil apoptotic process	1	147.8×	0.063	IL6
hepatic immune response	1	147.8×	0.063	IL6
cardiac chamber formation	1	147.8×	0.063	EDNRA
phosphatidylserine biosynthetic process	1	147.8×	0.063	PTDSS1
formate biosynthetic process	1	147.8×	0.063	MTHFD1L
cerebellar cortex formation	1	147.8×	0.063	PTPN11
neural plate anterior/posterior regionalization	1	147.8×	0.063	CELSR2
response to vitamin K	1	147.8×	0.063	F5
positive regulation of interleukin-21 production	1	147.8×	0.063	IL6
monocyte homeostasis	1	147.8×	0.063	SH2B3

Therapeutics

Drugs indicated for this disease

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

Drug	Development status
Rivaroxaban	Approved (phase 4)
Actovegin	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Carnosine	Phase 3 (in late-stage trials)
Cilostazol	Phase 3 (in late-stage trials)
Clopidogrel	Phase 3 (in late-stage trials)
Cocoa	Phase 3 (in late-stage trials)
Dalcetrapib	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Nicotinamide Riboside	Phase 3 (in late-stage trials)
OMEGA-3-ACID ETHYL ESTERS	Phase 3 (in late-stage trials)
Paclitaxel	Phase 3 (in late-stage trials)
Resveratrol	Phase 3 (in late-stage trials)
Sarpogrelate	Phase 3 (in late-stage trials)
Sildenafil	Phase 3 (in late-stage trials)
Sulodexide	Phase 3 (in late-stage trials)
Ticagrelor	Phase 3 (in late-stage trials)
Ticlopidine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Alprostadil, Arginine, Canakinumab, Creatine, Donaperminogene Seltoplasmid, Edoxaban, Emiplacel, Ghrelin, Ixmyelocel-T, L-Citrulline, OMEGA-3 FATTY ACIDS, Powdered Cellulose, Probucol, Regramostim, Riferminogene Pecaplasmid, Sacubitril, Simvastatin, Temsirolimus, Tirasemtiv, Valsartan, Zibotentan.

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 11 · Phased (≥1): 12 · Undrugged: 28

Druggability breadth: 22 of 40 evidence-associated genes (55%) 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
HDAC9	CELECOXIB
CHRNA3	VARENICLINE
EDNRA	AMBRISENTAN
F5	EDOXABAN
IL6	PREDNISOLONE
LDLR	NILOTINIB
LPL	ORLISTAT
MAPK10	MOMELOTINIB
MMP3	DOXYCYCLINE
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAPK10	58	4
EDNRA	31	4
HDAC9	28	4
CHRNA3	21	4
MMP3	14	4
PTPN11	8	4
IL6	3	4
F5	2	4
SORT1	1	3
UTRN	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
VARENICLINE	4	CHRNA3
MECAMYLAMINE	4	CHRNA3
NICOTINE	4	CHRNA3
ONDANSETRON	4	CHRNA3
TROPISETRON	4	CHRNA3
ACETYLCHOLINE	4	CHRNA3
BUPROPION	4	CHRNA3
GRANISETRON	4	CHRNA3
AMBRISENTAN	4	EDNRA
GRAMICIDIN	4	EDNRA
NITAZOXANIDE	4	EDNRA
IRBESARTAN	4	EDNRA
ACYCLOVIR	4	EDNRA
MACITENTAN	4	EDNRA
APROCITENTAN	4	EDNRA
SITAXENTAN	4	EDNRA
FLUOXETINE	4	EDNRA
SULFATHIAZOLE	4	EDNRA
SULFISOXAZOLE	4	EDNRA
SUNITINIB	4	EDNRA, MAPK10
SPARSENTAN	4	EDNRA
PIOGLITAZONE	4	EDNRA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 9.

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

Symbol	Assays	Type breakdown
HDAC9	1,625	Binding:1612, ADMET:8, Functional:4, Toxicity:1
MAPK10	900	Binding:892, Functional:7, ADMET:1
PTPN11	588	Binding:585, Functional:2, ADMET:1
MMP3	448	Binding:439, ADMET:7, Functional:2
CHRNA3	436	Binding:343, Functional:91, ADMET:2
EDNRA	418	Binding:342, Functional:73, Toxicity:2, ADMET:1
LDLR	55	Binding:54, Functional:1
TCF7L2	22	Binding:22
SORT1	17	Binding:15, ADMET:2
IL6	16	Binding:16
LPL	16	Binding:16
IPO5	13	Binding:13
F5	10	Binding:10
ABO	6	Binding:6
ATXN2	5	Binding:3, Functional:2
UTRN	5	Binding:3, ADMET:2
MTHFD1L	4	Binding:4
COG6	2	Binding:2
PTDSS1	2	Binding:2
HABP2	1	Binding:1
HLA-B	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HDAC9	3.5.1.98	histone deacetylase
MTHFD1L	6.3.4.3	formate-tetrahydrofolate ligase
HABP2	3.4.21.B1
LPL	3.1.1.34	lipoprotein lipase
MAPK10	2.7.11.24	mitogen-activated protein kinase
MMP3	3.4.24.17	stromelysin 1
ABO	2.4.1.37, 2.4.1.40, 2.4.1.88	fucosylgalactoside 3-alpha-galactosyltransferase, glycoprotein-fucosylgalactoside alpha-N-acetylgalactosaminyltransferase, globoside alpha-N-acetylgalactosaminyltransferase
PTDSS1	2.7.8.29	L-serine-phosphatidylethanolamine phosphatidyltransferase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HDAC9	1,625
CHRNA3	436
EDNRA	418
MAPK10	900
MMP3	448
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 40; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
HLA-B	1

Chemical tractability of cohort targets

30 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)
CELECOXIB	4	HDAC9
PHENYLBUTANOIC ACID	4	HDAC9
SODIUM PHENYLBUTYRATE	4	HDAC9
ROMIDEPSIN	4	HDAC9
BELINOSTAT	4	HDAC9
PANOBINOSTAT	4	HDAC9
VORINOSTAT	4	HDAC9
GIVINOSTAT	4	HDAC9
VARENICLINE	4	CHRNA3
MECAMYLAMINE	4	CHRNA3
NICOTINE	4	CHRNA3
ONDANSETRON	4	CHRNA3
TROPISETRON	4	CHRNA3
ACETYLCHOLINE	4	CHRNA3
BUPROPION	4	CHRNA3
GRANISETRON	4	CHRNA3
AMBRISENTAN	4	EDNRA
GRAMICIDIN	4	EDNRA
NITAZOXANIDE	4	EDNRA
IRBESARTAN	4	EDNRA
ACYCLOVIR	4	EDNRA
MACITENTAN	4	EDNRA
APROCITENTAN	4	EDNRA
SITAXENTAN	4	EDNRA
FLUOXETINE	4	EDNRA
SULFATHIAZOLE	4	EDNRA
SULFISOXAZOLE	4	EDNRA
SUNITINIB	4	EDNRA, MAPK10
SPARSENTAN	4	EDNRA
PIOGLITAZONE	4	EDNRA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	HDAC9, CHRNA3, EDNRA, F5, IL6, LDLR, LPL, MAPK10, MMP3, PTPN11
B	Phased (≥1) drug, not yet approved	2	SORT1, UTRN
C	Druggable family + PDB, no drug	5	HLA-B, IGLL1, LPA, ABO, PTDSS1
D	Druggable family + AlphaFold only, no drug	4	CSMD3, MTHFD1L, CELSR2, HABP2
E	Difficult family or no structure, no drug	19	CNNM1, ATXN2, TCF7L2, WWOX, MACF1, SYTL3, OSBPL10, COG6, CREB3L1, SMOC1 (+9 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CELSR2	0	SORT1
CNNM1	0	—
ATXN2	5	—
TCF7L2	22	—
WWOX	0	—
MACF1	0	—
SYTL3	0	—
OSBPL10	0	—
COG6	2	—
CREB3L1	0	—
CSMD3	0	—
SMOC1	0	—
MTHFD1L	4	—
BMP8A	0	—
COL4A1	0	—
NUTM2F	0	—
SH2B3	0	—
NSMCE1	0	—
RGL1	0	—
CDKN2B-AS1	0	—
HABP2	1	—
HLA-B	1	—
IGLL1	0	—
IPO5	13	—
LPA	0	—
ABO	6	—
PTDSS1	2	—
RAP2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 847.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	651
PHASE4	58
PHASE2	40
PHASE3	27
PHASE1/PHASE2	22
PHASE1	22
PHASE2/PHASE3	14
EARLY_PHASE1	13

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02842424	PHASE4	RECRUITING	Ramipril Treatment of Claudication: Oxidative Damage and Muscle Fibrosis
NCT05854641	PHASE4	RECRUITING	Efficacy and Safety of Stempeucel® in Patients With Critical Limb Ischemia (CLI) Due to Peripheral Arterial Disease
NCT06777901	PHASE4	RECRUITING	Auryon Atherectomy System With Standard Balloon Angioplasty Versus Standard Balloon Angioplasty Alone
NCT06873321	PHASE4	RECRUITING	VTE Incidence After Rivaroxaban + Aspirin or SAPT After Lower-limb Revascularization
NCT07076082	PHASE4	RECRUITING	Vascular Trial Associated Registry Pilot
NCT00144937	PHASE4	UNKNOWN	Multifactorial Intervention on Cardiovascular Risk Factors in Subjects With Peripheral Arterial Disease
NCT00152646	PHASE4	UNKNOWN	Platelets Induced Vasodilation, in Vitro and in Vivo Study
NCT00168467	PHASE4	COMPLETED	The Effects of Ramipril on Clinical Symptoms in Patients With Peripheral Arterial Disease
NCT00189618	PHASE4	COMPLETED	The Effects of Physical Training, ASA (Aspirin), and Clopidogrel on the Walking Capacity of Patients With Stage II Peripheral Arterial Disease (PAD)
NCT00640770	PHASE4	COMPLETED	Comparing Angioplasty and DES in the Treatment of Subjects With Ischemic Infrapopliteal Arterial Disease
NCT00648453	PHASE4	COMPLETED	Effect of Plavix on NO (Nitrogen Monoxide) Production of the Endothelial Function
NCT00657514	PHASE4	WITHDRAWN	Ranolazine Versus Placebo Effects on Exercise Tolerance in Patients With Heart Disease and Peripheral Arterial Disease
NCT00662480	PHASE4	UNKNOWN	Randomized Preventive Vascular Screening Trial of 65-74 Year Old Men in the Central Region of Denmark
NCT00681226	PHASE4	COMPLETED	Angiotensin Converting Enzyme (ACE) Inhibition and Peripheral Arterial Disease
NCT00687076	PHASE4	COMPLETED	Effectiveness of Intensive Lipid Modification Medication in Preventing the Progression of Peripheral Arterial Disease (The ELIMIT Study)
NCT00822172	PHASE4	COMPLETED	Evaluation of Cilostazol in Combination With L-Carnitine
NCT00855673	PHASE4	COMPLETED	Intermittent Mechanical Compression For Peripheral Arterial Disease
NCT00911417	PHASE4	COMPLETED	A Study to Collect Intravascular Ultrasound Images Before and After Treatment With the Jetstream System
NCT00955617	PHASE4	COMPLETED	DOTAREM®-Enhanced MRA Compared to GADOVIST®-Enhanced MRA in Patients With Abdominal or Lower Limb Arterial Diseases
NCT01026389	PHASE4	COMPLETED	Efficacy Evaluation of Dotarem Compared to Gadovist in the Diagnosis of Peripheral Arterial Disease
NCT01041729	PHASE4	COMPLETED	Long-term Pleiotropic Effect of Statins in Patients With Peripheral Arterial Disease
NCT01147705	PHASE4	COMPLETED	Allopurinol as a Possible Oxygen Sparing Agent During Exercise in Peripheral Arterial Disease
NCT01273623	PHASE4	COMPLETED	The Jetstream G3™ Calcium Study
NCT01412450	PHASE4	COMPLETED	Efficacity Study With the Protégé EverFlex Stent in Popliteal Lesions
NCT01412463	PHASE4	COMPLETED	DURABILITY+ : a Prospective, Multi-center, Controlled Study With the Everflex+ Stent in SFA Lesions
NCT01436435	PHASE4	COMPLETED	The Jetstream (JET) Post-market Registry
NCT01556542	PHASE4	COMPLETED	Drug Eluting Balloon in peripherAl inTErvention SFA
NCT01559974	PHASE4	TERMINATED	Vitamin D and Walking Ability in Patients With Peripheral Artery Occlusive Disease
NCT01627431	PHASE4	UNKNOWN	Residual Platelet Activity In Advanced Peripheral Artery Disease
NCT01653600	PHASE4	UNKNOWN	Efficacy of Self-Expanding Nitinol S.M.A.R.T CONTROL Stent Versus Life Stent For The Atherosclerotic Femoro-Popliteal Arterial Disease
NCT01718288	PHASE4	COMPLETED	Optimization of Treatment in Patients With Severe Peripheral Ischemia (Fontaine Stage IIb)
NCT01783600	PHASE4	COMPLETED	NanoCross BTK, a Prospective, Non-randomized, Multicenter, Controlled Trial Evaluating the Performance of the NanoCrossTM .014 Balloon Catheter in Infrapopliteal Lesions
NCT01799057	PHASE4	TERMINATED	The Effects of Metformin on Functional Capacity in Individuals With Peripheral Artery Disease-Related Intermittent Claudication
NCT01952756	PHASE4	COMPLETED	Effect of Cilostazol Endothelial Progenitor Cells and Collateral Formation in Peripheral Occlusive Artery Disease (PAOD)
NCT01983449	PHASE4	COMPLETED	Effectiveness of Adventitial Dexamethasone in Peripheral Artery Disease
NCT02033135	PHASE4	UNKNOWN	Paclitaxel Eluting Stent or Exercise for Thigh Atherosclerosis
NCT02212470	PHASE4	COMPLETED	Drug Eluting Balloon Angioplasty Versus Nitinol Stent Implantation in the Superficial Femoral Artery
NCT02374957	PHASE4	TERMINATED	Cilostazol After Lower Extremity Arterial Revascularization Trial
NCT02407314	PHASE4	TERMINATED	Ticagrelor and Peripheral Arterial Disease
NCT02548650	PHASE4	COMPLETED	Vorapaxar as an Add-On Antiplatelet Therapy in Patients With and Without Diabetes Mellitus

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CLOPIDOGREL	4	25
ASPIRIN	4	4
CILOSTAZOL	4	4
VORAPAXAR	4	3
NIACIN	4	2
NITROUS ACID	4	2
RAMIPRIL	4	2
RANOLAZINE	4	2
ALIROCUMAB	4	1
ALLOPURINOL	4	1
ATORVASTATIN	4	1
BETAMETHASONE	4	1
BOSENTAN	4	1
CHOLECALCIFEROL	4	1
DEXAMETHASONE	4	1
DEXAMETHASONE SODIUM PHOSPHATE	4	1
DIROXIMEL FUMARATE	4	1
EDETATE DISODIUM	4	1
EDOXABAN	4	1
EVOLOCUMAB	4	1
EZETIMIBE	4	1
FERUMOXYTOL	4	1
FISH OIL	4	1
GADOBUTROL	4	1
GADOTERATE MEGLUMINE	4	1
ILOPROST	4	1
INDOCYANINE GREEN	4	1
INDOCYANINE GREEN ACID FORM	4	1
LAROPIPRANT	4	1
LEVOCARNITINE	4	1