Cryoglobulinemia

Summary

Cryoglobulinemia (MONDO:0005576) is a disease with 3 cohort genes (2 GWAS associations across 1 studies) and 8 clinical trials. Top therapeutic interventions include belimumab and rituximab.

At a glance

• Cohort genes: 3
• GWAS associations: 2
• Clinical trials: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cryoglobulinemia
Mondo ID	MONDO:0005576
EFO	EFO:0005846
MeSH	D003449
DOID	DOID:2917
ICD-10-CM	D89.1
NCIT	C26736
SNOMED CT	30911005
UMLS	C0010403
MedGen	3673
Is cancer (heuristic)	no

Also known as: cryoglobulinemia

Data availability: 2 GWAS associations (1 study).

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › immune system disorder › hypersensitivity reaction disease › type IV hypersensitivity disease › cryoglobulinemia

Related subtypes (2): autoimmune lymphoproliferative syndrome, serum sickness

Subtypes (1): cryofibrinogenemia

Genetics & variants

GWAS landscape

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

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs9461776	7e-09	HLA-DRB1 - HLA-DQA1	G	2.02
rs2071286	2e-08	NOTCH4	?	2.15

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST002534	Zignego AL	2014	356	0	Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

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

MAF distribution

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

Functional consequences

Consequence	Count
intergenic_variant	1
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs9461776	6	32607958	A>G	0.29	intergenic_variant	HLA-DRB1 - HLA-DQA1	7e-09	Tier 4: intronic/intergenic
rs2071286	6	32212119	C>A,G,T	0.29	intron_variant	NOTCH4	2e-08	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 16 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HLA-DQA1	Orphanet:391490	Adult-onset myasthenia gravis
HLA-DQA1	Orphanet:930	Idiopathic achalasia
HLA-DRB1	Orphanet:2073	Narcolepsy type 1
HLA-DRB1	Orphanet:220393	Diffuse cutaneous systemic sclerosis
HLA-DRB1	Orphanet:220402	Limited cutaneous systemic sclerosis
HLA-DRB1	Orphanet:220407	Limited systemic sclerosis
HLA-DRB1	Orphanet:3437	Vogt-Koyanagi-Harada disease
HLA-DRB1	Orphanet:397	Giant cell arteritis
HLA-DRB1	Orphanet:477738	Pediatric multiple sclerosis
HLA-DRB1	Orphanet:536	Systemic lupus erythematosus
HLA-DRB1	Orphanet:545	Follicular lymphoma
HLA-DRB1	Orphanet:703	Bullous pemphigoid
HLA-DRB1	Orphanet:747	Autoimmune pulmonary alveolar proteinosis
HLA-DRB1	Orphanet:797	Sarcoidosis
HLA-DRB1	Orphanet:83465	Narcolepsy type 2
HLA-DRB1	Orphanet:85414	Systemic-onset juvenile idiopathic arthritis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HLA-DQA1	HGNC:4942	ENSG00000196735	P01909	HLA class II histocompatibility antigen, DQ alpha 1 chain	gwas
HLA-DRB1	HGNC:4948	ENSG00000196126	P01911	HLA class II histocompatibility antigen, DRB1 beta chain	gwas
NOTCH4	HGNC:7884	ENSG00000204301	Q99466	Neurogenic locus notch homolog protein 4	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HLA-DQA1	HLA class II histocompatibility antigen, DQ alpha 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.
HLA-DRB1	HLA class II histocompatibility antigen, DRB1 beta chain	A beta chain of antigen-presenting major histocompatibility complex class II (MHCII) molecule.
NOTCH4	Neurogenic locus notch homolog protein 4	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	2	19.5×	0.007
Scaffold/PPI	1	5.8×	0.164

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HLA-DQA1	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DRB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
NOTCH4	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lung	2
gall bladder	1
monocyte	1
rectum	1
granulocyte	1
vermiform appendix	1
apex of heart	1
omental fat pad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HLA-DQA1	244	broad	marker	gall bladder, rectum, monocyte
HLA-DRB1	131	tissue_specific	marker	vermiform appendix, granulocyte, right lung
NOTCH4	132	broad	marker	apex of heart, right lung, omental fat pad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HLA-DRB1	3,448
NOTCH4	2,670
HLA-DQA1	196

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HLA-DRB1	P01911	108
HLA-DQA1	P01909	28
NOTCH4	Q99466	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Translocation of ZAP-70 to Immunological synapse	2	423.0×	5e-05	HLA-DQA1, HLA-DRB1
Phosphorylation of CD3 and TCR zeta chains	2	362.5×	5e-05	HLA-DQA1, HLA-DRB1
Co-inhibition by PD-1	2	346.1×	5e-05	HLA-DQA1, HLA-DRB1
Generation of second messenger molecules	2	230.7×	9e-05	HLA-DQA1, HLA-DRB1
Downstream TCR signaling	2	85.5×	5e-04	HLA-DQA1, HLA-DRB1
Interferon gamma signaling	2	83.7×	5e-04	HLA-DQA1, HLA-DRB1
MHC class II antigen presentation	2	59.5×	8e-04	HLA-DQA1, HLA-DRB1
Defective LFNG causes SCDO3	1	761.3×	0.002	NOTCH4
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	634.4×	0.003	NOTCH4
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	346.1×	0.004	NOTCH4
Pre-NOTCH Processing in Golgi	1	211.5×	0.006	NOTCH4
NOTCH4 Intracellular Domain Regulates Transcription	1	190.3×	0.007	NOTCH4
Notch-HLH transcription pathway	1	135.9×	0.008	NOTCH4
Negative regulation of NOTCH4 signaling	1	79.3×	0.013	NOTCH4
Pre-NOTCH Transcription and Translation	1	40.9×	0.024	NOTCH4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
peptide antigen assembly with MHC class II protein complex	2	702.2×	1e-04	HLA-DQA1, HLA-DRB1
antigen processing and presentation of exogenous peptide antigen via MHC class II	2	362.4×	2e-04	HLA-DQA1, HLA-DRB1
positive regulation of immune response	2	321.0×	2e-04	HLA-DQA1, HLA-DRB1
positive regulation of T cell activation	2	295.6×	2e-04	HLA-DQA1, HLA-DRB1
regulation of interleukin-4 production	1	5617.3×	0.002	HLA-DRB1
antigen processing and presentation of endogenous peptide antigen via MHC class II	1	2808.7×	0.002	HLA-DRB1
regulation of interleukin-10 production	1	2808.7×	0.002	HLA-DRB1
myeloid dendritic cell antigen processing and presentation	1	1872.4×	0.003	HLA-DRB1
regulation of T-helper cell differentiation	1	1404.3×	0.003	HLA-DRB1
positive regulation of CD4-positive, alpha-beta T cell activation	1	1404.3×	0.003	HLA-DRB1
luteolysis	1	1123.5×	0.003	NOTCH4
positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	1123.5×	0.003	HLA-DRB1
negative regulation of endothelial cell differentiation	1	1123.5×	0.003	NOTCH4
negative regulation of cell adhesion molecule production	1	1123.5×	0.003	NOTCH4
positive regulation of T cell mediated immune response to tumor cell	1	802.5×	0.004	HLA-DRB1
positive regulation of transcription of Notch receptor target	1	802.5×	0.004	NOTCH4
morphogenesis of a branching structure	1	702.2×	0.004	NOTCH4
T-helper 1 type immune response	1	624.1×	0.004	HLA-DRB1
positive regulation of memory T cell differentiation	1	624.1×	0.004	HLA-DRB1
positive regulation of smooth muscle cell differentiation	1	624.1×	0.004	NOTCH4
immune response	2	31.4×	0.004	HLA-DQA1, HLA-DRB1
positive regulation of monocyte differentiation	1	510.7×	0.004	HLA-DRB1
negative regulation of cell-cell adhesion mediated by cadherin	1	510.7×	0.004	NOTCH4
detection of bacterium	1	468.1×	0.004	HLA-DRB1
vasculature development	1	374.5×	0.005	NOTCH4
endothelial cell morphogenesis	1	351.1×	0.005	NOTCH4
cell fate determination	1	312.1×	0.006	NOTCH4
inflammatory response to antigenic stimulus	1	312.1×	0.006	HLA-DRB1
mammary gland development	1	216.1×	0.008	NOTCH4
protein tetramerization	1	208.1×	0.008	HLA-DRB1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HLA-DQA1	0	0
HLA-DRB1	0	0
NOTCH4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HLA-DRB1	17	Binding:17
HLA-DQA1	2	Binding:2
NOTCH4	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	2	HLA-DQA1, HLA-DRB1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NOTCH4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HLA-DQA1	2	—
HLA-DRB1	17	—
NOTCH4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE2	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02825212	PHASE2/PHASE3	COMPLETED	Efficacy of All-Oral Anti-Viral Therapy for Symptomatic Hepatitis C Virus Infection-Related Cryoglobulinemia
NCT04629144	PHASE2	RECRUITING	Efficacy and Safety of Belimumab in the Treatment of Non-infectious Active Cryoglobulinemia Vasculitis Compared to Placebo. TRIBECA STUDY (Treatment nd BElimumab in Cryoglobulinemia Associated Vasculitis)
NCT02556866	PHASE2	TERMINATED	Rituximab Plus Corticosteroids in Non-infectious Active Mixed Cryoglobulinemia Vasculitis
NCT03717844	Not specified	RECRUITING	Registry for Adults With Plasma Cell Disorders (PCD’s)
NCT05283993	Not specified	RECRUITING	A Cohort Study of Plasma Cell Disorders (PCDs) in PKUFH
NCT00960713	Not specified	COMPLETED	The RITAI Cohort: An Observational Study on Rituximab Off-label Use for Auto-immune Disorders
NCT02856243	Not specified	UNKNOWN	Direct Antiviral Agents for Hepatitis C Virus-associated Cryoglobulinaemia Vasculitis
NCT03042520	Not specified	UNKNOWN	Long-term Outcomes of Chronic Hepatitis C Patients Post Sofosbuvir-based Treatment

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BELIMUMAB	4	1
RITUXIMAB	4	1