Diffuse scleroderma

Summary

Diffuse scleroderma (MONDO:0005019) is a disease with 9 cohort genes (8 GWAS associations across 4 studies) and 4 clinical trials. Top therapeutic interventions include human immunoglobulin g, rilonacept, and ixazomib.

At a glance

• Cohort genes: 9
• GWAS associations: 8
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diffuse scleroderma
Mondo ID	MONDO:0005019
EFO	EFO:0000404
MeSH	D045743
DOID	DOID:1580
UMLS	C1258104
MedGen	219839
GARD	0007727
Is cancer (heuristic)	no

Data availability: 8 GWAS associations (4 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › systemic sclerosis › diffuse scleroderma

Related subtypes (5): pulmonary systemic sclerosis, scleroderma, familial progressive, diffuse cutaneous systemic sclerosis, limited cutaneous systemic sclerosis, limited systemic sclerosis

Genetics & variants

GWAS landscape

8 GWAS associations across 4 studies. Top hits map to 6 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2021408	3e-57	HLA-DPB1, HLA-DPA1	C	2.67
rs10488631	1e-09	IRF5 - TNPO3	?
rs17340351	7e-07	TPI1P2 - CYCSP20	?
rs11640251	1e-06	VAC14	?
rs10235235	2e-06	ZNF394, ZNF789	?
rs7130875	3e-06	RNU6-376P - DDX6	G	1.22
rs12534421	4e-06	TNPO3	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90319685	Ishikawa Y	2024	575	112,599	GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.
GCST005335	Gorlova OY	2018	574	3,466	Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations.
GCST005553	Gorlova OY	2018	574	3,466	Gene-level association analysis of systemic sclerosis: A comparison of African-Americans and White populations.
GCST005535	Mayes MD	2014	574	3,466	Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis.

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	7

MAF distribution

Bucket	Variants
common (>=0.05)	7
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	5
intergenic_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2021408	6	33078949	T>C	0.178	intron_variant	HLA-DPB1, HLA-DPA1	3e-57	Tier 4: intronic/intergenic
rs10488631	7	128954129	T>C	0.05	intergenic_variant	IRF5 - TNPO3	1e-09	Tier 4: intronic/intergenic
rs17340351	7	129068743	T>A	0.05	intergenic_variant	TPI1P2 - CYCSP20	7e-07	Tier 4: intronic/intergenic
rs11640251	16	70708633	G>A	0.05	intron_variant	VAC14	1e-06	Tier 4: intronic/intergenic
rs10235235	7	99478208	T>C	0.05	intron_variant	ZNF394, ZNF789	2e-06	Tier 4: intronic/intergenic
rs7130875	11	118742965	T>C	0.248	intron_variant	RNU6-376P - DDX6	3e-06	Tier 4: intronic/intergenic
rs12534421	7	128984019	C>A	0.05	intron_variant	TNPO3	4e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

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

Gene	HGNC	Evidence routes
IRF5	IRF5	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TREH	Orphanet:103909	Trehalase deficiency
TNPO3	Orphanet:186	Primary biliary cholangitis
TNPO3	Orphanet:55595	TNP03-related limb-girdle muscular dystrophy D2
VAC14	Orphanet:3472	Yunis-Varon syndrome
VAC14	Orphanet:497906	Childhood-onset basal ganglia degeneration syndrome
DDX6	Orphanet:528084	Non-specific syndromic intellectual disability
IRF5	Orphanet:186	Primary biliary cholangitis
IRF5	Orphanet:220393	Diffuse cutaneous systemic sclerosis
IRF5	Orphanet:220402	Limited cutaneous systemic sclerosis
IRF5	Orphanet:536	Systemic lupus erythematosus

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TREH	HGNC:12266	ENSG00000118094	O43280	Trehalase	gwas
TNPO3	HGNC:17103	ENSG00000064419	Q9Y5L0	Transportin-3	gwas
CPSF4	HGNC:2327	ENSG00000160917	O95639	Cleavage and polyadenylation specificity factor subunit 4	gwas
MTSS2	HGNC:25094	ENSG00000132613	Q765P7	Protein MTSS 2	gwas
VAC14	HGNC:25507	ENSG00000103043	Q08AM6	Protein VAC14 homolog	gwas
DDX6	HGNC:2747	ENSG00000110367	P26196	Probable ATP-dependent RNA helicase DDX6	gwas
IL34	HGNC:28529	ENSG00000157368	Q6ZMJ4	Interleukin-34	gwas
IRF5	HGNC:6120	ENSG00000128604	Q13568	Interferon regulatory factor 5	gwas
ATP5MF	HGNC:848	ENSG00000241468	P56134	ATP synthase F(0) complex subunit f, mitochondrial	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TREH	Trehalase	Intestinal trehalase is probably involved in the hydrolysis of ingested trehalose.
TNPO3	Transportin-3	Importin, which transports target proteins into the nucleus.
CPSF4	Cleavage and polyadenylation specificity factor subunit 4	Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3’-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring ab…
MTSS2	Protein MTSS 2	Involved in plasma membrane dynamics.
VAC14	Protein VAC14 homolog	Scaffold protein component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).
DDX6	Probable ATP-dependent RNA helicase DDX6	Essential for the formation of P-bodies, cytosolic membrane-less ribonucleoprotein granules involved in RNA metabolism through the coordinated storage of mRNAs encoding regulatory functions.
IL34	Interleukin-34	Cytokine that promotes the proliferation, survival and differentiation of monocytes and macrophages.
IRF5	Interferon regulatory factor 5	Transcription factor that plays a critical role in innate immunity by activating expression of type I interferon (IFN) IFNA and INFB and inflammatory cytokines downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9.
ATP5MF	ATP synthase F(0) complex subunit f, mitochondrial	Subunit f, of the mitochondrial membrane ATP synthase complex (F(1)F(0) ATP synthase or Complex V) that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of th…

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.22

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
Enzyme (other)	2	2.7×	0.677
Scaffold/PPI	1	1.9×	0.687
Other/Unknown	5	1.0×	0.687
Transcription factor	1	0.9×	0.687

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TREH	Enzyme (other)	yes	3.2.1.28	Glyco_hydro_37, 6-hairpin_glycosidase_sf, 6hp_glycosidase-like_sf
TNPO3	Other/Unknown	no		ARM-like, Exportin-1/Importin-b-like, ARM-type_fold
CPSF4	Transcription factor	no		Znf_CCCH, Znf_CCHC, Znf_CCCH_sf
MTSS2	Scaffold/PPI	no		WH2_dom, I-BAR_dom, AH/BAR_dom_sf
VAC14	Other/Unknown	no		ARM-like, ARM-type_fold, VAC14_Fig4p-bd
DDX6	Enzyme (other)	yes	3.6.4.13	RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom
IL34	Other/Unknown	no		IL-34, IL-34_sf
IRF5	Other/Unknown	no		Interferon_reg_fact_DNA-bd_dom, SMAD_FHA_dom_sf, SMAD-like_dom_sf
ATP5MF	Other/Unknown	no		F1F0-ATPsyn_F_prd

Expression context

Cohort genes with no expression data: 0.

9 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
secondary oocyte	2
right hemisphere of cerebellum	2
duodenum	1
jejunal mucosa	1
small intestine	1
medial globus pallidus	1
tendon of biceps brachii	1
oocyte	1
C1 segment of cervical spinal cord	1
sural nerve	1
hindlimb stylopod muscle	1
primordial germ cell in gonad	1
stromal cell of endometrium	1
calcaneal tendon	1
ganglionic eminence	1
ventricular zone	1
kidney epithelium	1
tibial nerve	1
upper arm skin	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TREH	162	tissue_specific	marker	jejunal mucosa, duodenum, small intestine
TNPO3	299	ubiquitous	marker	secondary oocyte, tendon of biceps brachii, medial globus pallidus
CPSF4	280	ubiquitous	marker	secondary oocyte, oocyte, right hemisphere of cerebellum
MTSS2	209	ubiquitous	marker	C1 segment of cervical spinal cord, right hemisphere of cerebellum, sural nerve
VAC14	233	ubiquitous	marker	stromal cell of endometrium, primordial germ cell in gonad, hindlimb stylopod muscle
DDX6	271	ubiquitous	marker	ganglionic eminence, calcaneal tendon, ventricular zone
IL34	217	broad	marker	tibial nerve, upper arm skin, kidney epithelium
IRF5	214	broad	marker	monocyte, mononuclear cell, granulocyte
ATP5MF	295	broad	marker	apex of heart, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDX6	5,922
TNPO3	2,970
IRF5	2,737
VAC14	2,357
ATP5MF	2,062
MTSS2	1,965
TREH	1,889
CPSF4	1,781
IL34	1,169

Intra-cohort edges

A	B	Sources
IRF5	TNPO3	string_interaction
MTSS2	VAC14	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CPSF4	O95639	13
ATP5MF	P56134	10
DDX6	P26196	9
TNPO3	Q9Y5L0	6
IL34	Q6ZMJ4	4
VAC14	Q08AM6	1
IRF5	Q13568	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TREH	O43280	92.80
MTSS2	Q765P7	62.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 9 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inhibition of Host mRNA Processing and RNA Silencing	1	815.7×	0.038	CPSF4
SLC15A4:TASL-dependent IRF5 activation	1	271.9×	0.042	IRF5
Synthesis of PIPs at the late endosome membrane	1	135.9×	0.042	VAC14
Digestion of dietary carbohydrate	1	135.9×	0.042	TREH
mRNA decay by 5’ to 3’ exoribonuclease	1	108.8×	0.042	DDX6
Synthesis of PIPs at the early endosome membrane	1	102.0×	0.042	VAC14
Synthesis of PIPs at the Golgi membrane	1	90.6×	0.042	VAC14
Formation of ATP by chemiosmotic coupling	1	81.6×	0.042	ATP5MF
Processing of Intronless Pre-mRNAs	1	81.6×	0.042	CPSF4
Other interleukin signaling	1	68.0×	0.045	IL34
Cristae formation	1	49.4×	0.052	ATP5MF
Signaling by CSF1 (M-CSF) in myeloid cells	1	49.4×	0.052	IL34
Transport of Mature mRNA Derived from an Intronless Transcript	1	38.8×	0.061	CPSF4
RNA Polymerase II Transcription Termination	1	31.4×	0.067	CPSF4
tRNA processing in the nucleus	1	28.1×	0.067	CPSF4
mRNA 3’-end processing	1	28.1×	0.067	CPSF4
Toll Like Receptor 7/8 (TLR7/8) Cascade	1	26.3×	0.067	IRF5
Toll Like Receptor 9 (TLR9) Cascade	1	25.1×	0.067	IRF5
Mitochondrial biogenesis	1	24.0×	0.067	ATP5MF
Interferon alpha/beta signaling	1	21.8×	0.070	IRF5
Interferon gamma signaling	1	17.9×	0.077	IRF5
Toll-like Receptor Cascades	1	17.7×	0.077	IRF5
Interferon Signaling	1	17.2×	0.077	IRF5
Aerobic respiration and respiratory electron transport	1	12.7×	0.096	ATP5MF
mRNA Polyadenylation	1	12.6×	0.096	CPSF4
Organelle biogenesis and maintenance	1	9.4×	0.121	ATP5MF
Dengue Virus-Host Interactions	1	6.5×	0.165	CPSF4
Cytokine Signaling in Immune system	1	5.8×	0.177	IRF5
Innate Immune System	1	3.6×	0.261	IRF5
Immune System	1	1.9×	0.444	IRF5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
trehalose metabolic process	1	1872.4×	0.014	TREH
trehalose catabolic process	1	1872.4×	0.014	TREH
viral RNA genome packaging	1	936.2×	0.017	DDX6
interleukin-34-mediated signaling pathway	1	624.1×	0.017	IL34
lamellipodium organization	1	624.1×	0.017	MTSS2
positive regulation of macrophage proliferation	1	374.5×	0.024	IL34
cellular response to peptidoglycan	1	312.1×	0.025	IRF5
microglial cell proliferation	1	208.1×	0.026	IL34
spermatid differentiation	1	187.2×	0.026	DDX6
cellular response to muramyl dipeptide	1	187.2×	0.026	IRF5
positive regulation of monocyte differentiation	1	170.2×	0.026	IL34
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	170.2×	0.026	IRF5
positive regulation of macrophage differentiation	1	133.8×	0.030	IL34
P-body assembly	1	117.0×	0.030	DDX6
positive regulation of cytokine production involved in immune response	1	110.1×	0.030	IRF5
cell projection assembly	1	104.0×	0.030	MTSS2
plasma membrane organization	1	98.5×	0.030	MTSS2
miRNA-mediated gene silencing by inhibition of translation	1	98.5×	0.030	DDX6
positive regulation of macrophage chemotaxis	1	89.2×	0.030	IL34
proton motive force-driven ATP synthesis	1	89.2×	0.030	ATP5MF
activation of GTPase activity	1	81.4×	0.031	MTSS2
positive regulation of oligodendrocyte differentiation	1	74.9×	0.031	IL34
positive regulation of interferon-alpha production	1	72.0×	0.031	IRF5
cellular response to platelet-derived growth factor stimulus	1	72.0×	0.031	MTSS2
regulation of postsynaptic neurotransmitter receptor internalization	1	69.3×	0.031	VAC14
stress granule assembly	1	66.9×	0.031	DDX6
membrane organization	1	56.7×	0.035	MTSS2
stem cell population maintenance	1	46.8×	0.037	DDX6
positive regulation of type I interferon production	1	46.8×	0.037	IRF5
immune system process	1	43.5×	0.037	IRF5

Therapeutics

Drugs indicated for this disease

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

Drug	Development status
Lenabasum	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Abatacept, Acetylcysteine, Belumosudil, Brentuximab Vedotin, Dersimelagon, Human Immunoglobulin G, Ianalumab, Lanifibranor, Methoxsalen, Mycophenolate Mofetil, Telitacicept.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 7

Druggability breadth: 6 of 9 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TREH	1	2
DDX6	1	2
TNPO3	0	0
CPSF4	0	0
MTSS2	0	0
VAC14	0	0
IL34	0	0
IRF5	0	0
ATP5MF	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DUVOGLUSTAT	2	TREH
AZD-6482	2	DDX6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CPSF4	6	Binding:6
TREH	4	Binding:4
DDX6	4	Binding:4
TNPO3	1	Binding:1
VAC14	1	Binding:1
ATP5MF	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TREH	3.2.1.28	alpha,alpha-trehalase
DDX6	3.6.4.13	RNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
DUVOGLUSTAT	2	TREH
AZD-6482	2	DDX6

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	2	TREH, DDX6
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	TNPO3, CPSF4, MTSS2, VAC14, IL34, IRF5, ATP5MF

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNPO3	1	—
CPSF4	6	—
MTSS2	0	—
VAC14	1	—
IL34	0	—
IRF5	0	—
ATP5MF	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE1/PHASE2	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01538719	PHASE1/PHASE2	COMPLETED	IL1-TRAP, Rilonacept, in Systemic Sclerosis
NCT04837131	PHASE2	TERMINATED	A Study to Evaluate the Safety and Tolerability of Oral Ixazomib in Scleroderma-related Lung Disease Patients
NCT01785056	Not specified	UNKNOWN	IVIG Treatment in Systemic Sclerosis
NCT01881529	Not specified	COMPLETED	A Non-Interventional Pilot Study Assessing Whether Lysyl Oxidase-like 2 (LOXL2) is Present in Subjects With Scleroderma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
HUMAN IMMUNOGLOBULIN G	4	1
RILONACEPT	4	1
IXAZOMIB	3	1