Rheumatoid factor-negative juvenile idiopathic arthritis

disease

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Also known as juvenile rheumatoid factor-negative polyarthritispolyarthritis without rheumatoid factorrheumatoid factor-negative JIA

Summary

Rheumatoid factor-negative juvenile idiopathic arthritis (MONDO:0019432) is a disease with 37 cohort genes (31 GWAS associations across 1 studies). The dominant Reactome pathway is MAPK1 (ERK2) activation (3 cohort genes).

At a glance

Prevalence: 1-9 / 100 000 (Europe)
Cohort genes: 37
GWAS associations: 31
Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	8	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001369	Arthritis	Frequent (30-79%)
HP:0001386	Joint swelling	Frequent (30-79%)
HP:0001387	Joint stiffness	Frequent (30-79%)
HP:0001785	Ankle swelling	Frequent (30-79%)
HP:0002829	Arthralgia	Frequent (30-79%)
HP:0003019	Abnormality of the wrist	Frequent (30-79%)
HP:0003565	Elevated erythrocyte sedimentation rate	Frequent (30-79%)
HP:0005086	Knee osteoarthritis	Frequent (30-79%)
HP:0005186	Synovial hypertrophy	Frequent (30-79%)
HP:0100686	Enthesitis	Frequent (30-79%)
HP:0100769	Synovitis	Frequent (30-79%)
HP:0000554	Uveitis	Occasional (5-29%)
HP:0001155	Abnormality of the hand	Occasional (5-29%)
HP:0001371	Flexion contracture	Occasional (5-29%)
HP:0001384	Abnormality of the hip joint	Occasional (5-29%)
HP:0001530	Mild postnatal growth retardation	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001832	Abnormal metatarsal morphology	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0003043	Abnormality of the shoulder	Occasional (5-29%)
HP:0003319	Abnormality of the cervical spine	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0003493	Antinuclear antibody positivity	Occasional (5-29%)
HP:0008843	Hip osteoarthritis	Occasional (5-29%)
HP:0010754	Abnormality of the temporomandibular joint	Occasional (5-29%)
HP:0011134	Low-grade fever	Occasional (5-29%)
HP:0011911	Abnormality of metacarpophalangeal joint	Occasional (5-29%)
HP:0040313	Oligoarthritis	Occasional (5-29%)
HP:0001094	Iridocyclitis	Very rare (<1-4%)
HP:0001433	Hepatosplenomegaly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	rheumatoid factor-negative juvenile idiopathic arthritis
Mondo ID	MONDO:0019432
EFO	EFO:1002020
Orphanet	85408
UMLS	C3890205
MedGen	855549
GARD	0003931
Is cancer (heuristic)	no

Also known as: juvenile rheumatoid factor-negative polyarthritis · polyarthritis without rheumatoid factor · rheumatoid factor-negative JIA

Data availability: 31 GWAS associations (1 study).

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › connective tissue disorder › rheumatic disorder › juvenile idiopathic arthritis › polyarticular juvenile idiopathic arthritis › rheumatoid factor-negative juvenile idiopathic arthritis

Subtypes (2): rheumatoid factor-negative juvenile idiopathic arthritis with anti-nuclear antibodies, rheumatoid factor-negative juvenile idiopathic arthritis without anti-nuclear antibodies

Genetics & variants

GWAS landscape

31 GWAS associations across 1 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7775055	3e-174	HLA-DQB1 - MTCO3P1	G	6.01
rs6679677	3e-25	PHTF1 - RSBN1	A	1.59
rs10174238	1e-13	STAT4	G	1.29
rs2847293	1e-12	LINC01882 - PTPN2	A	1.31
rs10213692	3e-11	ANKRD55	?	1.27
rs1479924	6e-11	IL2 - IL21	?	1.27
rs34536443	1e-10	TYK2	?	1.79
rs7909519	8e-10	IL2RA	?	1.39
rs6894249	1e-09	CARINH, IRF1	?	1.32
rs7137828	2e-09	ATXN2	C	1.2
rs8129030	5e-09	RUNX1	?	1.28
rs10849448	5e-09	LTBR	A	1.24
rs2266959	6e-09	UBE2L3	A	1.24
rs27293	7e-09	LNPEP	A	1.31
rs72698115	1e-08	IL6R	C	1.36
rs3825568	1e-08	ZFP36L1	?	1.3
rs2284033	2e-08	IL2RB	?	1.19
rs7127214	2e-08	PRR5L	?	1.28
rs7069750	3e-08	FAS	C	1.18
rs6946509	3e-08	MTCYBP42 - TOMM7	T	1.19
rs9532434	5e-08	COG6	?	1.19
rs45539732	7e-08	STAT1	?	1.53
rs73300638	1e-07	JAZF1	C	1.28
rs34132030	2e-07	LINC02341	A	1.18
rs79893749	2e-07	CCR3	?	1.28
rs11074967	2e-07	RMI2	?	1.18
rs11714843	4e-07	TIMMDC1	A	1.22
rs4648881	5e-07	CLIC4 - RUNX3	G	1.16
rs149850873	5e-07	PTPN2	?	1.56
rs10194635	8e-07	LINC01104	T	1.24

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST005528	Hinks A	2013	2,816	13,056	Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	2
Tier 3: regulatory	1
Tier 4: intronic/intergenic	27

MAF distribution

Bucket	Variants
common (>=0.05)	30
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	18
intergenic_variant	8
5_prime_UTR_variant	2
non_coding_transcript_exon_variant	1
missense_variant	1
regulatory_region_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7775055	6	32690139	T>C	0.02	non_coding_transcript_exon_variant	HLA-DQB1 - MTCO3P1	3e-174	Tier 4: intronic/intergenic
rs6679677	1	113761186	C>A,T	0.1	intergenic_variant	PHTF1 - RSBN1	3e-25	Tier 4: intronic/intergenic
rs10174238	2	191108308	G>A,T	0.23	intron_variant	STAT4	1e-13	Tier 4: intronic/intergenic
rs2847293	18	12782449	A>G,T	0.17	intergenic_variant	LINC01882 - PTPN2	1e-12	Tier 4: intronic/intergenic
rs10213692	5	56146422	T>C,G	0.25	intron_variant	ANKRD55	3e-11	Tier 4: intronic/intergenic
rs1479924	4	122466445	G>A	0.29	intergenic_variant	IL2 - IL21	6e-11	Tier 4: intronic/intergenic
rs34536443	19	10352442	G>C,T	0.05	missense_variant	TYK2	1e-10	Tier 1: coding
rs7909519	10	6047878	T>G	0.11	intron_variant	IL2RA	8e-10	Tier 4: intronic/intergenic
rs6894249	5	132461855	A>C,G,T	0.39	intron_variant	CARINH, IRF1	1e-09	Tier 4: intronic/intergenic
rs7137828	12	111494996	C>A,G,T	0.49	intron_variant	ATXN2	2e-09	Tier 4: intronic/intergenic
rs8129030	21	35340290	T>A,G	0.37	intergenic_variant	RUNX1	5e-09	Tier 4: intronic/intergenic
rs10849448	12	6384185	A>G	0.24	5_prime_UTR_variant	LTBR	5e-09	Tier 2: splice/UTR
rs2266959	22	21568615	G>A,T	0.19	intron_variant	UBE2L3	6e-09	Tier 4: intronic/intergenic
rs27293	5	97021474	A>G,T	0.44	intron_variant	LNPEP	7e-09	Tier 4: intronic/intergenic
rs72698115	1	154406893	A>C	0.1	intron_variant	IL6R	1e-08	Tier 4: intronic/intergenic
rs3825568	14	68793871	C>G,T	0.44	5_prime_UTR_variant	ZFP36L1	1e-08	Tier 2: splice/UTR
rs2284033	22	37137994	G>A,C	0.44	intron_variant	IL2RB	2e-08	Tier 4: intronic/intergenic
rs7127214	11	36322143	C>G,T	0.35	intron_variant	PRR5L	2e-08	Tier 4: intronic/intergenic
rs7069750	10	89002619	G>C,T	0.44	intron_variant	FAS	3e-08	Tier 4: intronic/intergenic
rs6946509	7	22769871	T>A,C	0.45	intergenic_variant	MTCYBP42 - TOMM7	3e-08	Tier 4: intronic/intergenic
rs9532434	13	39781776	T>A,C	0.36	intergenic_variant	COG6	5e-08	Tier 4: intronic/intergenic
rs45539732	2	191009521	T>C	0.05	intron_variant	STAT1	7e-08	Tier 4: intronic/intergenic
rs73300638	7	28147725	A>C,G	0.11	intron_variant	JAZF1	1e-07	Tier 4: intronic/intergenic
rs34132030	13	42481900	C>T	0.32	intergenic_variant	LINC02341	2e-07	Tier 4: intronic/intergenic
rs79893749	3	46212159	C>T	0.15	intron_variant	CCR3	2e-07	Tier 4: intronic/intergenic
rs11074967	16	11377557	C>G,T	0.42	intron_variant	RMI2	2e-07	Tier 4: intronic/intergenic
rs11714843	3	119502217	T>A	0.18	intron_variant	TIMMDC1	4e-07	Tier 4: intronic/intergenic
rs4648881	1	24870664	G>A	0.49	regulatory_region_variant	CLIC4 - RUNX3	5e-07	Tier 3: regulatory
rs149850873	18	12885121	G>A,T	0.05	intergenic_variant	PTPN2	5e-07	Tier 4: intronic/intergenic
rs10194635	2	100217755	T>A,G	0.39	intron_variant	LINC01104	8e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 49 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 8

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

Gene	HGNC	Evidence routes
STAT4	STAT4	GWAS, Orphanet
ANKRD55	ANKRD55	GWAS, Orphanet
HLA-DQB1	HLA-DQB1	GWAS, Orphanet
IL2RA	IL2RA	GWAS, Orphanet
IL2RB	IL2RB	GWAS, Orphanet
IL6	IL6	GWAS, Orphanet
PTPN2	PTPN2	GWAS, Orphanet
PTPN22	PTPN22	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RUNX1	Orphanet:102724	Acute myeloid leukemia with t(8;21)(q22;q22) translocation
RUNX1	Orphanet:521	Chronic myeloid leukemia
RUNX1	Orphanet:71290	Familial platelet disorder with associated myeloid malignancy
RUNX1	Orphanet:98850	Aggressive systemic mastocytosis
ATXN2	Orphanet:803	Amyotrophic lateral sclerosis
ATXN2	Orphanet:98756	Spinocerebellar ataxia type 2
STAT4	Orphanet:117	Behçet disease
STAT4	Orphanet:536	Systemic lupus erythematosus
STAT4	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
STAT4	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
STAT4	Orphanet:93552	Pediatric systemic lupus erythematosus
TYK2	Orphanet:300865	Primary cutaneous anaplastic large cell lymphoma
TYK2	Orphanet:331226	Susceptibility to infection due to TYK2 deficiency
TYK2	Orphanet:98842	Lymphomatoid papulosis
UBE2L3	Orphanet:536	Systemic lupus erythematosus
TIMMDC1	Orphanet:2609	Isolated complex I deficiency
CCR1	Orphanet:117	Behçet disease
COG6	Orphanet:363523	Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome
COG6	Orphanet:464443	COG6-CGD
ANKRD55	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
ANKRD55	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
RMI2	Orphanet:508512	Intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome
JAZF1	Orphanet:213711	Endometrial stromal sarcoma
JAZF1	Orphanet:536	Systemic lupus erythematosus
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
HLA-DQB1	Orphanet:2073	Narcolepsy type 1
HLA-DQB1	Orphanet:477738	Pediatric multiple sclerosis
HLA-DQB1	Orphanet:703	Bullous pemphigoid
HLA-DQB1	Orphanet:83465	Narcolepsy type 2
HLA-DQB1	Orphanet:930	Idiopathic achalasia
IL21	Orphanet:477661	IL21-related infantile inflammatory bowel disease
IL2RA	Orphanet:169100	Immunodeficiency due to CD25 deficiency
IL2RA	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
IL2RA	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
IL2RB	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
IL2RB	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
IL6	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis
IL6R	Orphanet:656326	Autosomal recessive combined immunodeficiency due to IL6R deficiency
IRF1	Orphanet:699615	Severe mendelian susceptibility to mycobacterial diseases due to complete IRF1 deficiency
AFF3	Orphanet:632603	Mesomelic dysplasia-digital anomalies-intellectual disability syndrome
PTPN2	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
PTPN2	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
PTPN22	Orphanet:3437	Vogt-Koyanagi-Harada disease
PTPN22	Orphanet:397	Giant cell arteritis
PTPN22	Orphanet:536	Systemic lupus erythematosus
PTPN22	Orphanet:85408	Rheumatoid factor-negative polyarticular juvenile idiopathic arthritis
PTPN22	Orphanet:85410	Oligoarticular juvenile idiopathic arthritis
PTPN22	Orphanet:900	Granulomatosis with polyangiitis

Cohort genes → proteins

37 cohort genes, 36 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	37

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RUNX1	HGNC:10471	ENSG00000159216	Q01196	Runt-related transcription factor 1	gwas
RUNX3	HGNC:10473	ENSG00000020633	Q13761	Runt-related transcription factor 3	gwas
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	gwas
ZFP36L1	HGNC:1107	ENSG00000185650	Q07352	mRNA decay activator protein ZFP36L1	gwas
STAT4	HGNC:11365	ENSG00000138378	Q14765	Signal transducer and activator of transcription 4	gwas
TYK2	HGNC:12440	ENSG00000105397	P29597	Non-receptor tyrosine-protein kinase TYK2	gwas
UBE2L3	HGNC:12488	ENSG00000185651	P68036	Ubiquitin-conjugating enzyme E2 L3	gwas
TIMMDC1	HGNC:1321	ENSG00000113845	Q9NPL8	Complex I assembly factor TIMMDC1, mitochondrial	gwas
ATP8B2	HGNC:13534	ENSG00000143515	P98198	Phospholipid-transporting ATPase ID	gwas
CCR1	HGNC:1602	ENSG00000163823	P32246	C-C chemokine receptor type 1	gwas
CCR3	HGNC:1604	ENSG00000183625	P51677	C-C chemokine receptor type 3	gwas
CD80	HGNC:1700	ENSG00000121594	P33681	T-lymphocyte activation antigen CD80	gwas
COG6	HGNC:18621	ENSG00000133103	Q9Y2V7	Conserved oligomeric Golgi complex subunit 6	gwas
LONRF2	HGNC:24788	ENSG00000170500	Q1L5Z9	LON peptidase N-terminal domain and RING finger protein 2	gwas
ANKRD55	HGNC:25681	ENSG00000164512	Q3KP44	Ankyrin repeat domain-containing protein 55	gwas
PRR5L	HGNC:25878	ENSG00000135362	Q6MZQ0	Proline-rich protein 5-like	gwas
RMI2	HGNC:28349	ENSG00000175643	Q96E14	RecQ-mediated genome instability protein 2	gwas
JAZF1	HGNC:28917	ENSG00000153814	Q86VZ6	Juxtaposed with another zinc finger protein 1	gwas
ERAP2	HGNC:29499	ENSG00000164308	Q6P179	Endoplasmic reticulum aminopeptidase 2	gwas
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gwas
CARINH	HGNC:33838	ENSG00000197536		colitis associated IRF1 antisense regulator of intestinal homeostasis	gwas
FASN	HGNC:3594	ENSG00000169710	P49327	Fatty acid synthase	gwas
HLA-DQA2	HGNC:4943	ENSG00000237541	P01906	HLA class II histocompatibility antigen, DQ alpha 2 chain	gwas
HLA-DQB1	HGNC:4944	ENSG00000179344	P01920	HLA class II histocompatibility antigen, DQ beta 1 chain	gwas
IL2	HGNC:6001	ENSG00000109471	P60568	Interleukin-2	gwas
IL21	HGNC:6005	ENSG00000138684	Q9HBE4	Interleukin-21	gwas
IL2RA	HGNC:6008	ENSG00000134460	P01589	Interleukin-2 receptor subunit alpha	gwas
IL2RB	HGNC:6009	ENSG00000100385	P14784	Interleukin-2 receptor subunit beta	gwas
IL6	HGNC:6018	ENSG00000136244	P05231	Interleukin-6	gwas
IL6R	HGNC:6019	ENSG00000160712	P08887	Interleukin-6 receptor subunit alpha	gwas
IRF1	HGNC:6116	ENSG00000125347	P10914	Interferon regulatory factor 1	gwas
AFF3	HGNC:6473	ENSG00000144218	P51826	AF4/FMR2 family member 3	gwas
LNPEP	HGNC:6656	ENSG00000113441	Q9UIQ6	Leucyl-cystinyl aminopeptidase	gwas
LTBR	HGNC:6718	ENSG00000111321	P36941	Tumor necrosis factor receptor superfamily member 3	gwas
PRM1	HGNC:9447	ENSG00000175646	P04553	Sperm protamine P1	gwas
PTPN2	HGNC:9650	ENSG00000175354	P17706	Tyrosine-protein phosphatase non-receptor type 2	gwas
PTPN22	HGNC:9652	ENSG00000134242	Q9Y2R2	Tyrosine-protein phosphatase non-receptor type 22	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RUNX1	Runt-related transcription factor 1	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
RUNX3	Runt-related transcription factor 3	Forms the heterodimeric complex core-binding factor (CBF) with CBFB.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
ZFP36L1	mRNA decay activator protein ZFP36L1	Zinc-finger RNA-binding protein that destabilizes several cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthes…
STAT4	Signal transducer and activator of transcription 4	Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response.
TYK2	Non-receptor tyrosine-protein kinase TYK2	Tyrosine kinase of the non-receptor type involved in numerous cytokines and interferons signaling, which regulates cell growth, development, cell migration, innate and adaptive immunity.
UBE2L3	Ubiquitin-conjugating enzyme E2 L3	Ubiquitin-conjugating enzyme E2 that specifically acts with HECT-type and RBR family E3 ubiquitin-protein ligases.
TIMMDC1	Complex I assembly factor TIMMDC1, mitochondrial	Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I).
ATP8B2	Phospholipid-transporting ATPase ID	Catalytic component of P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of phosphatidylcholine (PC) from the outer to the inner leaflet of the plasma membrane.
CCR1	C-C chemokine receptor type 1	Chemokine receptor that plays a crucial role in regulating immune cell migration, inflammation, and immune responses.
CCR3	C-C chemokine receptor type 3	G protein-coupled receptor (GPCR) that plays a key role in the immune system by regulating the migration and activation of white blood cells in response to chemokines.
CD80	T-lymphocyte activation antigen CD80	Costimulatory molecule that belongs to the immunoglobulin superfamily that plays an important role in T-lymphocyte activation.
COG6	Conserved oligomeric Golgi complex subunit 6	Required for normal Golgi function.
PRR5L	Proline-rich protein 5-like	Associates with the mTORC2 complex that regulates cellular processes including survival and organization of the cytoskeleton.
RMI2	RecQ-mediated genome instability protein 2	Essential component of the RMI complex, a complex that plays an important role in the processing of homologous recombination intermediates.
JAZF1	Juxtaposed with another zinc finger protein 1	Acts as a transcriptional corepressor of orphan nuclear receptor NR2C2.
ERAP2	Endoplasmic reticulum aminopeptidase 2	Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
FASN	Fatty acid synthase	Fatty acid synthetase is a multifunctional enzyme that catalyzes the de novo biosynthesis of long-chain saturated fatty acids starting from acetyl-CoA and malonyl-CoA in the presence of NADPH.
HLA-DQA2	HLA class II histocompatibility antigen, DQ alpha 2 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
HLA-DQB1	HLA class II histocompatibility antigen, DQ beta 1 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
IL2	Interleukin-2	Cytokine produced by activated CD4-positive helper T-cells and to a lesser extend activated CD8-positive T-cells and natural killer (NK) cells that plays pivotal roles in the immune response and tolerance.
IL21	Interleukin-21	Cytokine with immunoregulatory activity.
IL2RA	Interleukin-2 receptor subunit alpha	Receptor for interleukin-2.
IL2RB	Interleukin-2 receptor subunit beta	Receptor for interleukin-2.
IL6	Interleukin-6	Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism.
IL6R	Interleukin-6 receptor subunit alpha	Part of the receptor for interleukin 6.
IRF1	Interferon regulatory factor 1	Transcriptional regulator which displays a remarkable functional diversity in the regulation of cellular responses.
AFF3	AF4/FMR2 family member 3	Putative transcription activator that may function in lymphoid development and oncogenesis.
LNPEP	Leucyl-cystinyl aminopeptidase	Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids.
LTBR	Tumor necrosis factor receptor superfamily member 3	Receptor for the heterotrimeric lymphotoxin containing LTA and LTB, and for TNFS14/LIGHT.
PRM1	Sperm protamine P1	Protamines substitute for histones in the chromatin of sperm during the haploid phase of spermatogenesis.
PTPN2	Tyrosine-protein phosphatase non-receptor type 2	Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR.
PTPN22	Tyrosine-protein phosphatase non-receptor type 22	Acts as a negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules.

Protein-family classification

Druggable: 15 · Difficult: 9 · Unknown: 13 · Druggable fraction: 0.41

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
Antibody/Immunoglobulin	5	3.9×	0.082
Phosphatase	2	4.5×	0.359
Complement	1	7.2×	0.384
Transcription factor	7	1.6×	0.384
Protease	2	2.0×	0.536
GPCR	2	1.3×	0.769
Scaffold/PPI	2	0.9×	0.913
Kinase	1	0.8×	0.918
Enzyme (other)	2	0.7×	0.918
Other/Unknown	13	0.6×	0.997

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RUNX1	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
RUNX3	Transcription factor	no		AML1_Runt, p53-like_TF_DNA-bd_sf, p53/RUNT-type_TF_DNA-bd_sf
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
ZFP36L1	Transcription factor	no		Znf_CCCH, Tis11B_N, Znf_CCCH_sf
STAT4	Transcription factor	no		SH2, STAT, p53-like_TF_DNA-bd_sf
TYK2	Kinase	yes	2.7.10.2	FERM_domain, Prot_kinase_dom, SH2
UBE2L3	Enzyme (other)	yes	2.3.2.23	UBC, UBQ-conjugating_enzyme/RWD, UBQ-conjugating_AS
TIMMDC1	Other/Unknown	no		TIMMDC1
ATP8B2	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
CCR1	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, Chemokine_CCR1
CCR3	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, Chemokine_CCR3
CD80	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
COG6	Other/Unknown	no		COG6, COG6_N, COG6_C
LONRF2	Transcription factor	no		Znf_RING, Lon_prtase_N, TPR-like_helical_dom_sf
ANKRD55	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf
PRR5L	Other/Unknown	no		Bit61/PRR5
RMI2	Other/Unknown	no		NA-bd_OB-fold, RMI2
JAZF1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZnF-Chromatin_assoc
ERAP2	Protease	yes	3.4.11.1	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_dom
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
CARINH	Other/Unknown	no
FASN	Enzyme (other)	yes	2.3.1.39	Thioesterase, Ac_transferase_dom_sf, Ppantetheine_attach_site
HLA-DQA2	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DQB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
IL2	Other/Unknown	no		IL-2, 4_helix_cytokine-like_core, IL-2_CS
IL21	Other/Unknown	no		IL-15/IL-21_fam, 4_helix_cytokine-like_core
IL2RA	Complement	yes		Sushi_SCR_CCP_dom, IL-2_rcpt_alpha, Sushi/SCR/CCP_sf
IL2RB	Antibody/Immunoglobulin	yes		Hempt_rcpt_S_F1_CS, FN3_dom, Ig-like_fold
IL6	Other/Unknown	no		IL-6-like, 4_helix_cytokine-like_core, IL6/GCSF/MGF_CS
IL6R	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_L_F3_CS, Ig_sub2, Ig_sub
IRF1	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, IRF1/IRF2, Interferon_reg_fac_CS
AFF3	Other/Unknown	no		AF4/FMR2, AF4_int, AF4/FMR2_CHD
LNPEP	Protease	yes	3.4.11.3	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_dom
LTBR	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_3_LTBR, TNFRSF3_N
PRM1	Other/Unknown	no		Protamine_P1
PTPN2	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
PTPN22	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat

Expression context

Cohort genes with no expression data: 0.

35 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)	37
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	10
monocyte	6
male germ line stem cell (sensu Vertebrata) in testis	5
buccal mucosa cell	4
leukocyte	4
lymph node	3
sperm	3
secondary oocyte	3
mucosa of paranasal sinus	2
olfactory bulb	2
mucosa of stomach	2
middle temporal gyrus	2
right hemisphere of cerebellum	2
mucosa of transverse colon	2
oocyte	2
mononuclear cell	2
blood	2
pancreatic ductal cell	2
tibia	2
Brodmann (1909) area 23	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RUNX1	253	ubiquitous	marker	olfactory segment of nasal mucosa, epithelium of bronchus, mucosa of paranasal sinus
RUNX3	220	broad	marker	granulocyte, buccal mucosa cell, lymph node
ATXN2	286	ubiquitous	marker	buccal mucosa cell, colonic epithelium, olfactory bulb
ZFP36L1	289	ubiquitous	marker	mucosa of paranasal sinus, endocervix, mucosa of stomach
STAT4	201	broad	marker	granulocyte, sperm, middle temporal gyrus
TYK2	288	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, adenohypophysis
UBE2L3	287	ubiquitous	marker	oocyte, secondary oocyte, mucosa of transverse colon
TIMMDC1	259	ubiquitous	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
ATP8B2	250	ubiquitous	marker	mucosa of stomach, right coronary artery, stromal cell of endometrium
CCR1	244	broad	marker	monocyte, mononuclear cell, leukocyte
CCR3	100	tissue_specific	yes	secondary oocyte, blood, oocyte
CD80	143	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, lower lobe of lung, pancreatic ductal cell
COG6	254	ubiquitous	marker	secondary oocyte, tibia, calcaneal tendon
LONRF2	235	broad	marker	corpus epididymis, Brodmann (1909) area 23, middle temporal gyrus
ANKRD55	169	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, sperm, primordial germ cell in gonad
PRR5L	203	ubiquitous	marker	mucosa of transverse colon, granulocyte, rectum
RMI2	187	ubiquitous	marker	ventricular zone, ileal mucosa, ganglionic eminence
JAZF1	251	ubiquitous	marker	trabecular bone tissue, cauda epididymis, right adrenal gland cortex
ERAP2	244	ubiquitous	marker	buccal mucosa cell, granulocyte, lymph node
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
CARINH	239	ubiquitous	marker	granulocyte, bone marrow cell, pancreatic ductal cell
FASN	273	ubiquitous	marker	right hemisphere of cerebellum, endometrium epithelium, skin of abdomen
HLA-DQA2	127	broad	marker	granulocyte, vermiform appendix, male germ line stem cell (sensu Vertebrata) in testis
HLA-DQB1	268	broad	marker	right lung, spleen, upper lobe of left lung
IL2	92		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
IL21	26		marker	male germ line stem cell (sensu Vertebrata) in testis, olfactory bulb, type B pancreatic cell
IL2RA	153	broad	marker	lymph node, vermiform appendix, caecum
IL2RB	208	broad	marker	granulocyte, decidua, ileal mucosa
IL6	200	ubiquitous	marker	cartilage tissue, vena cava, gall bladder
IL6R	271	ubiquitous	marker	blood, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 20.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IL6	9,239
FASN	6,551
RUNX1	4,994
IRF1	4,076
TYK2	3,932
CD80	3,664
ATXN2	3,360
RUNX3	3,293
CCR1	2,912
IL6R	2,805

Intra-cohort edges

A	B	Sources
AFF3	ANKRD55	string_interaction
AFF3	LONRF2	string_interaction
AFF3	PTPN22	string_interaction
ANKRD55	PTPN22	string_interaction
ATXN2	SH2B3	string_interaction
CCR1	CCR3	string_interaction
IL2	IL2RA	intact
IL2	IL2RB	intact
IL2RA	IL2RB	string_interaction
IL2RA	PTPN2	string_interaction
IL6	IL6R	biogrid_interaction, intact, string_interaction
IL6	STAT4	string_interaction
IL6	TYK2	string_interaction
IL6R	TYK2	string_interaction
LONRF2	PRR5L	string_interaction
PTPN2	SH2B3	string_interaction
PTPN2	STAT4	string_interaction
PTPN22	STAT4	string_interaction
RUNX1	RUNX3	string_interaction
STAT4	TYK2	string_interaction

Structural data

PDB: 23 · AlphaFold-only: 13 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TYK2	P29597	52
IL2	P60568	37
FASN	P49327	34
UBE2L3	P68036	21
IL6	P05231	17
ERAP2	Q6P179	14
PTPN2	P17706	14
PTPN22	Q9Y2R2	14
LNPEP	Q9UIQ6	11
HLA-DQB1	P01920	10
IL2RA	P01589	10
IL6R	P08887	10
IL2RB	P14784	8
CD80	P33681	6
RMI2	Q96E14	6
RUNX1	Q01196	5
CCR1	P32246	3
IL21	Q9HBE4	3
ZFP36L1	Q07352	2
LTBR	P36941	2
RUNX3	Q13761	1
ATXN2	Q99700	1
CCR3	P51677	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HLA-DQA2	P01906	89.29
STAT4	Q14765	86.87
COG6	Q9Y2V7	86.62
ATP8B2	P98198	82.24
LONRF2	Q1L5Z9	78.97
TIMMDC1	Q9NPL8	72.08
JAZF1	Q86VZ6	70.25
PRR5L	Q6MZQ0	68.40
IRF1	P10914	66.65
SH2B3	Q9UQQ2	63.45
ANKRD55	Q3KP44	63.43
PRM1	P04553	54.01
AFF3	P51826	52.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 196. Enrichment computed across 37 evidence-associated genes (30 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 30 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	3	114.2×	1e-04	TYK2, IL6, IL6R
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	3	114.2×	1e-04	RUNX1, IL2, IL2RA
MAPK3 (ERK1) activation	3	103.8×	1e-04	TYK2, IL6, IL6R
Interleukin-6 signaling	3	95.2×	1e-04	TYK2, IL6, IL6R
Interleukin-2 signaling	3	95.2×	1e-04	IL2, IL2RA, IL2RB
Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)	3	87.8×	2e-04	RUNX1, RUNX3, STAT4
Interleukin-10 signaling	4	31.1×	2e-04	TYK2, CCR1, CD80, IL6
RUNX3 regulates RUNX1-mediated transcription	2	253.8×	5e-04	RUNX1, RUNX3
Interleukin receptor SHC signaling	3	40.8×	0.001	IL2, IL2RA, IL2RB
Interleukin-23 signaling	2	84.6×	0.005	STAT4, TYK2
RUNX3 regulates p14-ARF	2	76.1×	0.005	RUNX1, RUNX3
Interleukin-21 signaling	2	76.1×	0.005	STAT4, IL21
Interleukin-35 Signalling	2	63.4×	0.007	STAT4, TYK2
Cytokine Signaling in Immune system	5	6.8×	0.010	STAT4, CCR1, CD80, SH2B3, IRF1
Activation of STAT3 by cadherin engagement	3	16.3×	0.010	TYK2, IL6, IL6R
Translocation of ZAP-70 to Immunological synapse	2	42.3×	0.012	HLA-DQA2, PTPN22
Phosphorylation of CD3 and TCR zeta chains	2	36.2×	0.016	HLA-DQA2, PTPN22
Interferon gamma signaling	3	12.6×	0.019	HLA-DQA2, HLA-DQB1, IRF1
Interleukin-20 family signaling	2	28.2×	0.023	STAT4, TYK2
Interleukin-12 signaling	2	27.2×	0.024	STAT4, TYK2
Interleukin-4 and Interleukin-13 signaling	3	10.3×	0.028	TYK2, IL6, IL6R
Transcriptional regulation by RUNX3	2	18.1×	0.048	RUNX1, RUNX3
RUNX1 regulates expression of components of tight junctions	1	76.1×	0.088	RUNX1
RUNX1 regulates transcription of genes involved in interleukin signaling	1	76.1×	0.088	RUNX1
RUNX2 regulates genes involved in differentiation of myeloid cells	1	76.1×	0.088	RUNX1
RUNX3 regulates BCL2L11 (BIM) transcription	1	76.1×	0.088	RUNX3
Chemokine receptors bind chemokines	2	12.5×	0.088	CCR1, CCR3
Signaling by Interleukins	3	6.4×	0.088	STAT4, CCR1, CD80
RAF/MAP kinase cascade	3	6.1×	0.088	IL2, IL2RA, IL2RB
RUNX1 regulates estrogen receptor mediated transcription	1	63.4×	0.093	RUNX1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 35 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
immune response	9	12.1×	1e-05	TYK2, CCR1, CCR3, CD80, HLA-DQA2, HLA-DQB1, IL2, IL2RA (+1 more)
positive regulation of interleukin-17 production	4	68.8×	4e-05	TYK2, IL2, IL21, IL6
cytokine-mediated signaling pathway	6	22.4×	4e-05	STAT4, TYK2, CCR1, IL2RB, IL6, IL6R
interleukin-2-mediated signaling pathway	3	180.6×	5e-05	IL2, IL2RA, IL2RB
regulation of CD4-positive, alpha-beta T cell proliferation	2	481.5×	4e-04	IL2, IL2RA
hepatic immune response	2	321.0×	7e-04	IL6, IL6R
regulation of T cell homeostatic proliferation	2	321.0×	7e-04	IL2, IL2RA
positive regulation of T cell proliferation	4	29.6×	7e-04	TYK2, CD80, IL21, IL6
positive regulation of type II interferon production	4	25.7×	8e-04	TYK2, IL2, IL21, PTPN22
negative regulation of CD4-positive, alpha-beta T cell differentiation	2	240.7×	0.001	RUNX1, RUNX3
monocyte chemotaxis	3	49.8×	0.001	CCR1, IL6, IL6R
cell surface receptor signaling pathway via STAT	3	48.1×	0.001	IL2, IL6, IL6R
positive regulation of CD8-positive, alpha-beta T cell differentiation	2	192.6×	0.001	RUNX1, RUNX3
positive regulation of immunoglobulin production	3	41.3×	0.002	IL2, IL21, IL6
positive regulation of tissue remodeling	2	160.5×	0.002	IL2, IL21
vascular endothelial growth factor production	2	137.6×	0.002	IL6, IL6R
T cell differentiation	3	32.8×	0.003	IL2, PTPN2, PTPN22
negative regulation of T cell receptor signaling pathway	3	31.4×	0.003	CD80, PTPN2, PTPN22
interleukin-12-mediated signaling pathway	2	107.0×	0.003	STAT4, TYK2
activated T cell proliferation	2	107.0×	0.003	IL2, IL2RA
germinal center B cell differentiation	2	96.3×	0.004	IL21, IL6
negative regulation of lipid storage	2	87.5×	0.004	IL6, PTPN2
peripheral nervous system neuron development	2	87.5×	0.004	RUNX1, RUNX3
T-helper 17 cell lineage commitment	2	87.5×	0.004	IL6, IL6R
cell surface receptor signaling pathway via JAK-STAT	3	24.9×	0.004	STAT4, TYK2, IL6
neutrophil mediated immunity	2	80.2×	0.004	IL6, IL6R
T follicular helper cell differentiation	2	80.2×	0.004	IL21, IL6
positive regulation of leukocyte chemotaxis	2	74.1×	0.005	IL6, IL6R
type II interferon-mediated signaling pathway	2	68.8×	0.005	TYK2, IRF1
positive regulation of neuroinflammatory response	2	68.8×	0.005	CCR1, IL6

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 9 · Undrugged: 28

Druggability breadth: 22 of 37 evidence-associated genes (59%) 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
RUNX1	APOMORPHINE HYDROCHLORIDE
TYK2	FEDRATINIB
CCR1	ABAMETAPIR
FASN	RABEPRAZOLE
IL6	PREDNISOLONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TYK2	72	4
CCR1	8	4
FASN	8	4
PTPN2	4	2
IL6	3	4
RUNX1	2	4
CCR3	2	2
IL2	2	2
ERAP2	1	2
RUNX3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
APOMORPHINE HYDROCHLORIDE	4	RUNX1
FEDRATINIB	4	TYK2
RUXOLITINIB	4	TYK2
TOFACITINIB	4	TYK2
UPADACITINIB	4	TYK2
BARICITINIB	4	TYK2
FILGOTINIB	4	TYK2
ABROCITINIB	4	TYK2
DEUCRAVACITINIB	4	TYK2
MOMELOTINIB	4	TYK2
AXITINIB	4	TYK2
RUXOLITINIB PHOSPHATE	4	TYK2
INFIGRATINIB PHOSPHATE	4	TYK2
INFIGRATINIB	4	TYK2
PACRITINIB	4	TYK2
TOFACITINIB CITRATE	4	TYK2
BOSUTINIB	4	TYK2
PEFICITINIB	4	TYK2
CRAVACITINIB	4	TYK2
PAZOPANIB	4	TYK2
NINTEDANIB	4	TYK2
SUNITINIB	4	TYK2
DASATINIB	4	TYK2
ERLOTINIB	4	TYK2
CRIZOTINIB	4	TYK2
MIDOSTAURIN	4	TYK2
IMATINIB	4	TYK2
ABAMETAPIR	4	CCR1
RALTEGRAVIR	4	CCR1
RABEPRAZOLE	4	FASN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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

Symbol	Assays	Type breakdown
TYK2	1,083	Binding:1043, Functional:39, ADMET:1
PTPN2	250	Binding:246, ADMET:4
CCR1	243	Binding:176, Functional:67
CCR3	175	Binding:107, Functional:68
FASN	142	Binding:136, Functional:6
PTPN22	137	Binding:122, Functional:10, ADMET:5
ERAP2	46	Binding:40, ADMET:4, Functional:2
IL2	35	Binding:34, ADMET:1
LNPEP	34	Binding:33, ADMET:1
RUNX1	20	Binding:17, Functional:3
STAT4	20	Binding:20
IL6	16	Binding:16
ATXN2	5	Binding:3, Functional:2
IL6R	5	Binding:5
UBE2L3	2	Binding:2
COG6	2	Binding:2
IL2RA	2	Binding:2
LONRF2	1	Binding:1
IL2RB	1	Binding:1
LTBR	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TYK2	2.7.10.2	non-specific protein-tyrosine kinase
UBE2L3	2.3.2.23, 2.3.2.24	E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
ATP8B2	7.6.2.1	P-type phospholipid transporter
ERAP2	3.4.11.1, 3.4.11.6	leucyl aminopeptidase, aminopeptidase B
FASN	2.3.1.39, 2.3.1.85	[acyl-carrier-protein] S-malonyltransferase, fatty-acid synthase system
LNPEP	3.4.11.3	cystinyl aminopeptidase
PTPN2	3.1.3.48	protein-tyrosine-phosphatase
PTPN22	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
TYK2	1,083
CCR1	243
CCR3	175
FASN	142
PTPN2	250
PTPN22	137

Pharmacogenomics

Cohort genes with a PharmGKB record: 37; with CPIC/DPWG dosing guidelines: 0.

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

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)
APOMORPHINE HYDROCHLORIDE	4	RUNX1
FEDRATINIB	4	TYK2
RUXOLITINIB	4	TYK2
TOFACITINIB	4	TYK2
UPADACITINIB	4	TYK2
BARICITINIB	4	TYK2
FILGOTINIB	4	TYK2
ABROCITINIB	4	TYK2
DEUCRAVACITINIB	4	TYK2
MOMELOTINIB	4	TYK2
AXITINIB	4	TYK2
RUXOLITINIB PHOSPHATE	4	TYK2
INFIGRATINIB PHOSPHATE	4	TYK2
INFIGRATINIB	4	TYK2
PACRITINIB	4	TYK2
TOFACITINIB CITRATE	4	TYK2
BOSUTINIB	4	TYK2
PEFICITINIB	4	TYK2
CRAVACITINIB	4	TYK2
PAZOPANIB	4	TYK2
NINTEDANIB	4	TYK2
SUNITINIB	4	TYK2
DASATINIB	4	TYK2
ERLOTINIB	4	TYK2
CRIZOTINIB	4	TYK2
MIDOSTAURIN	4	TYK2
IMATINIB	4	TYK2
ABAMETAPIR	4	CCR1
RALTEGRAVIR	4	CCR1
RABEPRAZOLE	4	FASN

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	RUNX1, TYK2, CCR1, FASN, IL6
B	Phased (≥1) drug, not yet approved	4	CCR3, ERAP2, IL2, PTPN2
C	Druggable family + PDB, no drug	8	UBE2L3, CD80, HLA-DQB1, IL2RA, IL2RB, IL6R, LNPEP, PTPN22
D	Druggable family + AlphaFold only, no drug	1	HLA-DQA2
E	Difficult family or no structure, no drug	19	RUNX3, ATXN2, ZFP36L1, STAT4, TIMMDC1, ATP8B2, COG6, LONRF2, ANKRD55, PRR5L (+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)
STAT4	20	TYK2
IL6R	5	IL6
PTPN22	137	—
RUNX3	0	—
ATXN2	5	—
ZFP36L1	0	—
UBE2L3	2	—
TIMMDC1	0	—
ATP8B2	0	—
CD80	0	—
COG6	2	—
LONRF2	1	—
ANKRD55	0	—
PRR5L	0	—
RMI2	0	—
JAZF1	0	—
SH2B3	0	—
CARINH	0	—
HLA-DQA2	0	—
HLA-DQB1	0	—
IL21	0	—
IL2RA	2	—
IL2RB	1	—
IRF1	0	—
AFF3	0	—
LNPEP	34	—
LTBR	1	—
PRM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: RUNX1, RUNX3, ATXN2, ZFP36L1, STAT4, TYK2, UBE2L3, TIMMDC1, ATP8B2, CCR1, CCR3, CD80, COG6, LONRF2, ANKRD55, PRR5L, RMI2, JAZF1, ERAP2, SH2B3, CARINH, FASN, HLA-DQA2, HLA-DQB1, IL2, IL21, IL2RA, IL2RB, IL6, IL6R, IRF1, AFF3, LNPEP, LTBR, PRM1, PTPN2, PTPN22