chronic hepatitis B virus infection

Summary

chronic hepatitis B virus infection (MONDO:0005366) is a disease with 14 cohort genes (37 GWAS associations across 12 studies) and 754 clinical trials. The dominant Reactome pathway is Interferon gamma signaling (6 cohort genes). Top therapeutic interventions include entecavir anhydrous, tenofovir disoproxil, and telbivudine.

At a glance

• Cohort genes: 14
• GWAS associations: 37
• Clinical trials: 754

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	chronic hepatitis B virus infection
Mondo ID	MONDO:0005366
EFO	EFO:0004239
MeSH	D019694
ICD-11	352087872
UMLS	C0524909
MedGen	99834
Is cancer (heuristic)	no

Also known as: chronic Hepatitis B · hepatitis B infection, chronic · hepatitis B, chronic

Data availability: 37 GWAS associations (12 studies).

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of primarily extrinsic mechanism › infectious disease › viral infectious disease › primary viral infectious disease › Hepadnaviridae infectious disease › hepatitis B virus infection › chronic hepatitis B virus infection

Related subtypes (1): acute hepatitis B virus infection

Genetics & variants

GWAS landscape

37 GWAS associations across 12 studies. Top hits map to 14 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs9277535	1e-70	HLA-DPB1	A	1.52
rs7453920	1e-60	HLA-DQB2	A	2
rs3077	1e-53	HLA-DPA1	A	1.45
rs9277562	5e-45	HLA-DPB1	T	0.44
rs142975055	1e-44	HLA-DPB1	GAAATA	0.44
rs7770370	3e-35	HLA-DPB1	G	1.64
rs12614	1e-34	CFB	T	1.89
rs2856718	7e-28	HLA-DQB1 - MTCO3P1	C	1.28
rs378352	1e-23	HLA-DOA	T	1.26
rs28747027	7e-21	HLA-DQB1 - MTCO3P1	G	1.41
rs2853953	5e-20	HCG27 - HLA-C	A	1.47
rs422951	5e-16	NOTCH4	G	1.27
rs1883832	3e-15	CD40	T	1.19
rs7756516	1e-12	HLA-DQB2; HLA-DQB2; HLA-DPA3; HLA-DQB3 - HLA-DQA2; HLA-DPB1	G	1.49
rs9276370	2e-12	HLA-DQB3 - HLA-DQA2	T	1.95
rs9366816	3e-10	HLA-DPA3	C	1.43
rs743862	3e-09	TSBP1-AS1 - HLA-DRA	?	0.27
rs1419881	3e-07	TCF19	G	1.12
rs35766154	7e-07	PLSCR1 - RNU6-428P	?	0.44
rs3130542	9e-07	HCG27 - HLA-C	A	1.17
rs652888	1e-06	EHMT2-AS1, EHMT2	G	1.14
rs6911967	1e-06	GPR6 - WASF1	?	0.38
rs1264473	2e-06	RN7SL563P - GRHL2-DT	C	3.93
rs6942409	3e-06	RBMX2P4 - ETV1	?
rs149411024	3e-06	HLA-DQA1	?	2.18
rs144998273	5e-06	SGPL1	?	2.52
rs1828682	5e-06	MGST1	?	0.33
rs7773858	5e-06	ADGRB3 - LMBRD1	?	2.89
rs7537971	6e-06	DENND2C - AMPD1	?	0.31
rs35901075	8e-06	CRBN - SUMF1	?	0.53

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST002879	Jiang DK	2015	2,514	1,130	Genetic variants in five novel loci including CFB and CD40 predispose to chronic hepatitis B.
GCST90018584	Sakaue S	2021	2,234	169,588	A cross-population atlas of genetic associations for 220 human phenotypes.
GCST010560	Huang YH	2020	1,810	9,002	Large-scale genome-wide association study identifies HLA class II variants associated with chronic HBV infection: a study from Taiwan Biobank.
GCST90013690	Ishigaki K	2020	1,394	211,059	Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
GCST90013732	Ishigaki K	2020	878	108,469	Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
GCST90013767	Ishigaki K	2020	516	102,590	Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
GCST012284	Zeng Z	2021	495	0	Genome-wide association study identifies new loci associated with risk of HBV infection and disease progression.
GCST002068	Kim YJ	2013	400	1,000	A genome-wide association study identified new variants associated with the risk of chronic hepatitis B.
GCST002490	Chang SW	2014	321	0	A genome-wide association study on chronic HBV infection and its clinical progression in male Han-Taiwanese.
GCST90133384	Ashouri S	2022	318	0	Genome-Wide Association Study for Chronic Hepatitis B Infection in the Thai Population.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	5
Tier 3: regulatory	0
Tier 4: intronic/intergenic	24

MAF distribution

Bucket	Variants
common (>=0.05)	31
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	11
intron_variant	10
3_prime_UTR_variant	4
stop_gained	1
synonymous_variant	1
missense_variant	1
5_prime_UTR_variant	1
3_prime_UTR_variant; intron_variant; intron_variant; intergenic_variant; 3_prime_UTR_variant	1
non_coding_transcript_exon_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs9277535	6	33087084	A>G	0.42	3_prime_UTR_variant	HLA-DPB1	1e-70	Tier 2: splice/UTR
rs7453920	6	32762235	A>G,T	0.12	intron_variant	HLA-DQB2	1e-60	Tier 4: intronic/intergenic
rs3077	6	33065245	A>C,G,T	0.34	3_prime_UTR_variant	HLA-DPA1	1e-53	Tier 2: splice/UTR
rs9277562	6	33088985	C>T	0.424	3_prime_UTR_variant	HLA-DPB1	5e-45	Tier 2: splice/UTR
rs142975055	6	33084120	G>GAAATA	0.05	intron_variant	HLA-DPB1	1e-44	Tier 4: intronic/intergenic
rs7770370	6	33081144	A>G,T	0.426	intron_variant	HLA-DPB1	3e-35	Tier 4: intronic/intergenic
rs12614	6	31946402	C>A,G,T	0.08	stop_gained	CFB	1e-34	Tier 1: coding
rs2856718	6	32702478	C>A,G,T	0.45	intergenic_variant	HLA-DQB1 - MTCO3P1	7e-28	Tier 4: intronic/intergenic
rs378352	6	33007157	G>A,C	0.39	synonymous_variant	HLA-DOA	1e-23	Tier 4: intronic/intergenic
rs28747027	6	32687200	C>G,T	0.464	intergenic_variant	HLA-DQB1 - MTCO3P1	7e-21	Tier 4: intronic/intergenic
rs2853953	6	31267728	G>A,C,T	0.1	intergenic_variant	HCG27 - HLA-C	5e-20	Tier 4: intronic/intergenic
rs422951	6	32220606	T>A,C,G	0.19	missense_variant	NOTCH4	5e-16	Tier 1: coding
rs1883832	20	46118343	T>A,C,G	0.37	5_prime_UTR_variant	CD40	3e-15	Tier 2: splice/UTR
rs7756516	6;6;6;6;6	32756140	C>T	0.43	3_prime_UTR_variant; intron_variant; intron_variant; intergenic_variant; 3_prime_UTR_variant	HLA-DQB2; HLA-DQB2; HLA-DPA3; HLA-DQB3 - HLA-DQA2; HLA-DPB1	1e-12	Tier 4: intronic/intergenic
rs9276370	6	32739518	G>A,T	0.076	intergenic_variant	HLA-DQB3 - HLA-DQA2	2e-12	Tier 4: intronic/intergenic
rs9366816	6	33136398	T>C	0.414	intron_variant	HLA-DPA3	3e-10	Tier 4: intronic/intergenic
rs743862	6	32414162	T>C	0.05	intron_variant	TSBP1-AS1 - HLA-DRA	3e-09	Tier 4: intronic/intergenic
rs1419881	6	31162816	G>A,C,T	0.45	3_prime_UTR_variant	TCF19	3e-07	Tier 2: splice/UTR
rs35766154	3	146557768	T>C	0.05	intergenic_variant	PLSCR1 - RNU6-428P	7e-07	Tier 4: intronic/intergenic
rs3130542	6	31264334	A>G	0.16	intergenic_variant	HCG27 - HLA-C	9e-07	Tier 4: intronic/intergenic
rs652888	6	31883457	A>C,G,T	0.24	non_coding_transcript_exon_variant	EHMT2-AS1, EHMT2	1e-06	Tier 4: intronic/intergenic
rs6911967	6	110007172	T>C	0.05	intergenic_variant	GPR6 - WASF1	1e-06	Tier 4: intronic/intergenic
rs1264473	8	101419355	C>A,T	0.196	intron_variant	RN7SL563P - GRHL2-DT	2e-06	Tier 4: intronic/intergenic
rs6942409	7	13215782	T>A,C,G	0.05	intron_variant	RBMX2P4 - ETV1	3e-06	Tier 4: intronic/intergenic
rs149411024	6	32634218	G>A,C,T	0.05	intergenic_variant	HLA-DQA1	3e-06	Tier 4: intronic/intergenic
rs144998273	10	70851429	C>CTA	0.05	intron_variant	SGPL1	5e-06	Tier 4: intronic/intergenic
rs1828682	12	16362077	T>C	0.05	intron_variant	MGST1	5e-06	Tier 4: intronic/intergenic
rs7773858	6	69534787	G>A,C	0.05	intergenic_variant	ADGRB3 - LMBRD1	5e-06	Tier 4: intronic/intergenic
rs7537971	1	114671205	G>A,C,T	0.05	intergenic_variant	DENND2C - AMPD1	6e-06	Tier 4: intronic/intergenic
rs35901075	3	3273463	TTATA>T,TTA,TTATATA,TTATATATA,TTATATATATA,TTATATATATATA,TTATATATATATATA	0.05	intron_variant	CRBN - SUMF1	8e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 1

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

Gene	HGNC	Evidence routes
HLA-DPB1	HLA-DPB1	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CFB	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CD40	Orphanet:101090	Hyper-IgM syndrome type 3
GRHL2	Orphanet:423454	Nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome
GRHL2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GRHL2	Orphanet:98973	Posterior polymorphous corneal dystrophy
HLA-C	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
HLA-DPA1	Orphanet:900	Granulomatosis with polyangiitis
HLA-DPB1	Orphanet:133	Chronic beryllium disease
HLA-DPB1	Orphanet:900	Granulomatosis with polyangiitis
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

Cohort genes → proteins

14 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	14

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CFB	HGNC:1037	ENSG00000243649	P00751	Complement factor B	gwas
TCF19	HGNC:11629	ENSG00000137310	Q9Y242	Transcription factor 19	gwas
CD40	HGNC:11919	ENSG00000101017	P25942	Tumor necrosis factor receptor superfamily member 5	gwas
EHMT2	HGNC:14129	ENSG00000204371	Q96KQ7	Histone-lysine N-methyltransferase EHMT2	gwas
HLA-DPA3	HGNC:19393	ENSG00000237398		major histocompatibility complex, class II, DP alpha 3 (pseudogene)	gwas
GRHL2	HGNC:2799	ENSG00000083307	Q6ISB3	Grainyhead-like protein 2 homolog	gwas
HLA-C	HGNC:4933	ENSG00000204525	P10321	HLA class I histocompatibility antigen, C alpha chain	gwas
HLA-DOA	HGNC:4936	ENSG00000204252	P06340	HLA class II histocompatibility antigen, DO alpha chain	gwas
HLA-DPA1	HGNC:4938	ENSG00000231389	P20036	HLA class II histocompatibility antigen, DP alpha 1 chain	gwas
HLA-DPB1	HGNC:4940	ENSG00000223865	P04440	HLA class II histocompatibility antigen, DP beta 1 chain	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
HLA-DQB2	HGNC:4945	ENSG00000232629	P05538	HLA class II histocompatibility antigen, DQ beta 2 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)
CFB	Complement factor B	Precursor of the catalytic component of the C3 and C5 convertase complexes of the alternative pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the…
TCF19	Transcription factor 19	Potential transcription factor that may play a role in the regulation of genes involved in cell cycle G1/S transition.
CD40	Tumor necrosis factor receptor superfamily member 5	Receptor for TNFSF5/CD40LG.
EHMT2	Histone-lysine N-methyltransferase EHMT2	Histone methyltransferase that specifically mono- and dimethylates ‘Lys-9’ of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin.
GRHL2	Grainyhead-like protein 2 homolog	Transcription factor playing an important role in primary neurulation and in epithelial development.
HLA-C	HLA class I histocompatibility antigen, C alpha chain	Antigen-presenting major histocompatibility complex class I (MHCI) molecule with an important role in reproduction and antiviral immunity.
HLA-DOA	HLA class II histocompatibility antigen, DO alpha chain	Important modulator in the HLA class II restricted antigen presentation pathway by interaction with the HLA-DM molecule in B-cells.
HLA-DPA1	HLA class II histocompatibility antigen, DP 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-DPB1	HLA class II histocompatibility antigen, DP 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.
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.
HLA-DQB2	HLA class II histocompatibility antigen, DQ beta 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.
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: 8 · Difficult: 4 · Unknown: 2 · Druggable fraction: 0.57

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	7	14.6×	7e-07
Scaffold/PPI	2	2.5×	0.481
Protease	1	2.6×	0.536
Transcription factor	2	1.2×	0.649
Other/Unknown	2	0.3×	1.000

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CFB	Protease	yes	3.4.21.47	Sushi_SCR_CCP_dom, Trypsin_dom, Peptidase_S1A
TCF19	Transcription factor	no		FHA_dom, Znf_PHD, SMAD_FHA_dom_sf
CD40	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_5, TNFRSF5_N
EHMT2	Scaffold/PPI	no	2.1.1.355	SET_dom, Ankyrin_rpt, Pre-SET_dom
HLA-DPA3	Other/Unknown	no
GRHL2	Transcription factor	no		CP2, TF_CP2-like, GRHL1/CP2_C
HLA-C	Antibody/Immunoglobulin	yes		MHC_I_a_a1/a2, Ig_C1-set, Ig-like_dom
HLA-DOA	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DPA1	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
HLA-DPB1	Antibody/Immunoglobulin	yes		MHC_II_b_N, Ig/MHC_CS, Ig_C1-set
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
HLA-DQB2	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.

12 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)	14
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lymph node	5
granulocyte	5
right lung	4
spleen	3
vermiform appendix	3
gall bladder	1
liver	1
right lobe of liver	1
primordial germ cell in gonad	1
ventricular zone	1
ganglionic eminence	1
nucleus accumbens	1
putamen	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
buccal mucosa cell	1
cervix squamous epithelium	1
oviduct epithelium	1
blood	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CFB	134	broad	marker	right lobe of liver, liver, gall bladder
TCF19	133	ubiquitous	yes	primordial germ cell in gonad, ventricular zone, lymph node
CD40	242	ubiquitous	marker	lymph node, right lung, spleen
EHMT2	134	ubiquitous	marker	nucleus accumbens, ganglionic eminence, putamen
HLA-DPA3	108	tissue_specific	yes	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
GRHL2	200	broad	marker	buccal mucosa cell, oviduct epithelium, cervix squamous epithelium
HLA-C	134	ubiquitous	marker	blood, right lung, spleen
HLA-DOA	133	broad	marker	lymph node, vermiform appendix, granulocyte
HLA-DPA1	133	ubiquitous	marker	monocyte, leukocyte, granulocyte
HLA-DPB1	135	ubiquitous	marker	granulocyte, lymph node, vermiform appendix
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
HLA-DQB2	127	tissue_specific	marker	lymph node, granulocyte, skin of abdomen
NOTCH4	132	broad	marker	apex of heart, right lung, omental fat pad

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EHMT2	4,723
CD40	3,765
NOTCH4	2,670
CFB	1,997
TCF19	1,774
HLA-DQA2	1,611
HLA-DQB2	1,547
GRHL2	1,365
HLA-DOA	891
HLA-C	836

Intra-cohort edges

A	B	Sources
EHMT2	TCF19	string_interaction
HLA-C	HLA-DQB1	intact
HLA-DPA1	HLA-DPB1	intact
HLA-DPA1	HLA-DQB1	intact
HLA-DQA2	HLA-DQB2	string_interaction
HLA-DQB2	TCF19	string_interaction

Structural data

PDB: 10 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EHMT2	Q96KQ7	35
CFB	P00751	26
CD40	P25942	14
HLA-C	P10321	13
HLA-DPA1	P20036	10
HLA-DPB1	P04440	10
HLA-DQB1	P01920	10
NOTCH4	Q99466	3
GRHL2	Q6ISB3	1
HLA-DOA	P06340	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HLA-DQA2	P01906	89.29
HLA-DQB2	P05538	86.87
TCF19	Q9Y242	63.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. Enrichment computed across 14 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interferon gamma signaling	6	62.8×	7e-09	HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB1, HLA-DQB2
Translocation of ZAP-70 to Immunological synapse	4	211.5×	4e-08	HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2
Phosphorylation of CD3 and TCR zeta chains	4	181.3×	5e-08	HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2
Co-inhibition by PD-1	4	173.0×	5e-08	HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2
Generation of second messenger molecules	4	115.3×	2e-07	HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2
MHC class II antigen presentation	5	37.2×	8e-07	HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2
Downstream TCR signaling	4	42.8×	9e-06	HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2
Alternative complement activation	1	190.3×	0.022	CFB
Defective LFNG causes SCDO3	1	190.3×	0.022	NOTCH4
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	158.6×	0.023	NOTCH4
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	2	14.5×	0.027	CD40, HLA-C
Activation of C3 and C5	1	105.7×	0.029	CFB
Endosomal/Vacuolar pathway	1	86.5×	0.030	HLA-C
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	86.5×	0.030	NOTCH4
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	56.0×	0.043	CD40
Pre-NOTCH Processing in Golgi	1	52.9×	0.043	NOTCH4
NOTCH4 Intracellular Domain Regulates Transcription	1	47.6×	0.045	NOTCH4
Regulation of TP53 Activity through Methylation	1	45.3×	0.045	EHMT2
DAP12 interactions	1	39.6×	0.049	HLA-C
Notch-HLH transcription pathway	1	34.0×	0.053	NOTCH4
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	32.8×	0.053	HLA-C
Transcriptional Regulation by E2F6	1	24.4×	0.068	EHMT2
Transcriptional Regulation by VENTX	1	22.1×	0.071	EHMT2
Negative regulation of NOTCH4 signaling	1	19.8×	0.074	NOTCH4
Regulation of Complement cascade	1	19.4×	0.074	CFB
RNA Polymerase I Transcription Initiation	1	18.7×	0.074	EHMT2
TNFR2 non-canonical NF-kB pathway	1	15.1×	0.088	CD40
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	1	13.6×	0.091	EHMT2
PKMTs methylate histone lysines	1	13.4×	0.091	EHMT2
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	1	12.7×	0.091	EHMT2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 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	6	486.1×	5e-14	HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB1, HLA-DQB2
antigen processing and presentation of exogenous peptide antigen via MHC class II	6	250.9×	2e-12	HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB1, HLA-DQB2
positive regulation of immune response	6	222.2×	3e-12	HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB1, HLA-DQB2
positive regulation of T cell activation	6	204.7×	4e-12	HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB1, HLA-DQB2
adaptive immune response	7	45.4×	1e-09	HLA-C, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB1, HLA-DQB2
immune response	5	18.1×	9e-05	HLA-C, HLA-DPA1, HLA-DQA2, HLA-DQB1, HLA-DQB2
phenotypic switching	1	1296.3×	0.011	EHMT2
epithelium migration	1	1296.3×	0.011	GRHL2
positive regulation of T cell proliferation	2	39.9×	0.013	HLA-DPA1, HLA-DPB1
negative regulation of antigen processing and presentation of peptide antigen via MHC class II	1	648.1×	0.014	HLA-DOA
response to cobalamin	1	648.1×	0.014	CD40
positive regulation of type II interferon production	2	34.6×	0.014	HLA-DPA1, HLA-DPB1
epithelial cell morphogenesis involved in placental branching	1	432.1×	0.017	GRHL2
positive regulation of protein kinase C signaling	1	432.1×	0.017	CD40
positive regulation of interleukin-4-mediated signaling pathway	1	432.1×	0.017	CD40
B cell mediated immunity	1	324.1×	0.018	CD40
cellular response to erythropoietin	1	324.1×	0.018	CD40
anterior neural tube closure	1	324.1×	0.018	GRHL2
luteolysis	1	259.3×	0.018	NOTCH4
peptidyl-lysine dimethylation	1	259.3×	0.018	EHMT2
negative regulation of endothelial cell differentiation	1	259.3×	0.018	NOTCH4
negative regulation of cell adhesion molecule production	1	259.3×	0.018	NOTCH4
T cell receptor signaling pathway	2	23.4×	0.018	HLA-DPB1, HLA-DQB1
positive regulation of transcription of Notch receptor target	1	185.2×	0.024	NOTCH4
morphogenesis of a branching structure	1	162.0×	0.025	NOTCH4
lung lobe morphogenesis	1	162.0×	0.025	GRHL2
immune response-regulating cell surface receptor signaling pathway	1	144.0×	0.025	CD40
cardiac ventricle morphogenesis	1	144.0×	0.025	GRHL2
positive regulation of smooth muscle cell differentiation	1	144.0×	0.025	NOTCH4
lung epithelial cell differentiation	1	144.0×	0.025	GRHL2

Therapeutics

Drugs indicated for this disease

7 approved, 11 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Adefovir Dipivoxil	Approved (phase 4)
Hepatitis B Immune Globulin	Approved (phase 4)
Hepatitis B Virus Hbsag Surface Protein Antigen	Approved (phase 4)
INTERFERON ALFA-2B	Approved (phase 4)
Lamivudine	Approved (phase 4)
PEGINTERFERON ALFA-2A	Approved (phase 4)
Telbivudine	Approved (phase 4)
Adefovir	Phase 3 (in late-stage trials)
Bepirovirsen	Phase 3 (in late-stage trials)
Besifovir	Phase 3 (in late-stage trials)
Clevudine	Phase 3 (in late-stage trials)
Daunorubicin	Phase 3 (in late-stage trials)
Diammonium Glycyrrhizinate	Phase 3 (in late-stage trials)
Emtricitabine	Phase 3 (in late-stage trials)
PEGINTERFERON ALFA-2B	Phase 3 (in late-stage trials)
Ribavirin	Phase 3 (in late-stage trials)
Tenofovir Alafenamide	Phase 3 (in late-stage trials)
Tenofovir Anhydrous	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Celecoxib, Chlorpheniramine, Diphenhydramine, Durvalumab, Envafolimab, Hydronidone, Nitazoxanide, Nivolumab, PEGINTERFERON LAMBDA-1A, Pamrevlumab, Sodium Chloride, Tenofovir Disoproxil.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 12

Druggability breadth: 5 of 14 evidence-associated genes (36%) 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
CFB	IPTACOPAN
EHMT2	RALTITREXED

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EHMT2	7	4
CFB	1	4
TCF19	0	0
CD40	0	0
HLA-DPA3	0	0
GRHL2	0	0
HLA-C	0	0
HLA-DOA	0	0
HLA-DPA1	0	0
HLA-DPB1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IPTACOPAN	4	CFB
RALTITREXED	4	EHMT2
TAZEMETOSTAT	4	EHMT2
DISULFIRAM	4	EHMT2
EBSELEN	3	EHMT2
DITIOCARB SODIUM	2	EHMT2
THIRAM	2	EHMT2
SINEFUNGIN	2	EHMT2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
EHMT2	442	Binding:435, Functional:6, ADMET:1
CFB	33	Binding:33
CD40	10	Binding:10
NOTCH4	2	Binding:2
HLA-C	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFB	3.4.21.47	alternative-complement-pathway C3/C5 convertase
EHMT2	2.1.1.355, 2.1.1.356, 2.1.1.367, 2.1.1.368	[histone H3]-lysine9 N-trimethyltransferase, [histone H3]-lysine27 N-trimethyltransferase, [histone H3]-lysine9 N-methyltransferase, [histone H3]-lysine9 N-dimethyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EHMT2	442

Pharmacogenomics

Cohort genes with a PharmGKB record: 14; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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)
IPTACOPAN	4	CFB
RALTITREXED	4	EHMT2
TAZEMETOSTAT	4	EHMT2
DISULFIRAM	4	EHMT2
EBSELEN	3	EHMT2
DITIOCARB SODIUM	2	EHMT2
THIRAM	2	EHMT2
SINEFUNGIN	2	EHMT2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	CFB, EHMT2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	5	HLA-C, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DQB1
D	Druggable family + AlphaFold only, no drug	2	HLA-DQA2, HLA-DQB2
E	Difficult family or no structure, no drug	5	TCF19, CD40, HLA-DPA3, GRHL2, NOTCH4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TCF19	0	—
CD40	10	—
HLA-DPA3	0	—
GRHL2	0	—
HLA-C	1	—
HLA-DOA	0	—
HLA-DPA1	0	—
HLA-DPB1	0	—
HLA-DQA2	0	—
HLA-DQB1	0	—
HLA-DQB2	0	—
NOTCH4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 754.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	239
PHASE4	177
PHASE2	129
PHASE1	99
PHASE3	71
PHASE1/PHASE2	29
EARLY_PHASE1	6
PHASE2/PHASE3	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03753074	PHASE4	ACTIVE_NOT_RECRUITING	Effectiveness of TAF in Reducing Clinical Events in CHB Patients Beyond Treatment Indications by Current Guidelines
NCT03792919	PHASE4	RECRUITING	Cessation of Long Term NAs vs. Keeping on NAs Among CHB Patients (CNAVK)
NCT04035837	PHASE4	ACTIVE_NOT_RECRUITING	The Clinical Cure Project of Chronic Hepatitis B in China
NCT04496882	PHASE4	ACTIVE_NOT_RECRUITING	Chronic Hepatitis b Patients Switch to tAf After Discontinuation of Nucleoside Analogue
NCT04780204	PHASE4	ACTIVE_NOT_RECRUITING	Effectiveness of Antiviral Treatment in Cirrhotic Patients with Low-level Hepatitis B Virus DNA Levels
NCT04782375	PHASE4	ACTIVE_NOT_RECRUITING	Safely Discontinue Antiviral Treatment in Patients With Chronic Hepatitis B
NCT05147090	PHASE4	ACTIVE_NOT_RECRUITING	Effects of Empagliflozin on Fibrosis and Cirrhosis in Chronic Hepatitis B Patients
NCT05182463	PHASE4	RECRUITING	Peginterferon Treatment Study for Inactive Chronic Hepatitis B Patients
NCT05410496	PHASE4	ACTIVE_NOT_RECRUITING	Tenofovir Alafenamide Switching Therapy in Kidney or Liver Transplant Recipients With Chronic HBV Infection
NCT05853718	PHASE4	RECRUITING	Study of Tenofovir Alafenamide in HBV-Infected Pregnant Women
NCT06364930	PHASE4	RECRUITING	SGLT2i to Prevent of Liver Complications in Patients With CHB and Diabetes Mellitus
NCT06368882	PHASE4	RECRUITING	Efficacy and Safety of Antiviral Therapy With Peg-interferon for Chronic Hepatitis B Complicated With Nonalcoholic Fatty Liver Disease（OCEAN PROJECT）
NCT06743438	PHASE4	ACTIVE_NOT_RECRUITING	Long-term Safety and Efficacy of Tenofovir Amibufenamide in Patients With CHB
NCT06900166	PHASE4	NOT_YET_RECRUITING	Pegylated Interferon Alfa-2b in Reducing Relapse Rates After Nucleos(t)ide Analogue Withdrawal in HBeAg-negative CHB Patients with Low Level HBsAg
NCT07071636	PHASE4	NOT_YET_RECRUITING	Clinical Efficacy of Pegylated Interferon Alpha-2b Combined With Nucleos(t)Ide Analogues in the Treatment of Chronic Hepatitis B Patients
NCT07258251	PHASE4	NOT_YET_RECRUITING	Strengthening Hepatitis B Screening, Linkage to Care and Long-Term Monitoring in Phichit Province, Thailand: A Birth Bohort Approach
NCT07345611	PHASE4	NOT_YET_RECRUITING	Entecavir With or Without Pegylated Interferon α-2b in Children Aged 3-6 Years With Immune-Active Chronic Hepatitis B
NCT07345624	PHASE4	NOT_YET_RECRUITING	Entecavir With or Without Pegylated Interferon α-2b in Children Aged 3-6 Years With Immune-Tolerant Chronic Hepatitis B
NCT07573943	PHASE4	RECRUITING	ASC22 Combined With Peg-IFNa in Achieving Functional Cure in Patients With Chronic Hepatitis B Virus Infection
NCT00117533	PHASE4	UNKNOWN	Pegylated Interferon Alfa-2b Plus Ribavirin in Chronic Hepatitis B and Delta
NCT00120354	PHASE4	COMPLETED	Long-Term Lamivudine Therapy for Chronic Hepatitis B
NCT00226382	PHASE4	COMPLETED	Treatment With Peginterferon Alfa-2a (40 KD) of Chronic Hepatitis B Patients, Who Have Failed Anti-viral Treatment
NCT00291616	PHASE4	COMPLETED	Efficacy Study of Thymosin alpha1 & Pegylated Interferon-alpha2a to Treat Chronic Hepatitis B
NCT00307242	PHASE4	COMPLETED	Study Comparing the Safety of Switching From Lamivudine to Adefovir Dipivoxil Versus Overlapping Lamivudine and Adefovir Before Adefovir Dipivoxil Monotherapy in Patients With Chronic Hepatitis B
NCT00324961	PHASE4	COMPLETED	Adefovir Dipivoxil Tablets (10mg) In Chinese Subjects With HBe Antigen Negative Chronic Hepatitis B
NCT00338780	PHASE4	COMPLETED	Trial of Lamivudine Treatment in HBeAg Negative Chronic Hepatitis B Patients (in Asia)
NCT00347009	PHASE4	COMPLETED	Adefovir Dipivoxil For The Treatment Of Patients With Chronic Hepatitis B Related Advanced Fibrosis Or Cirrhosis
NCT00354653	PHASE4	COMPLETED	A Trial To Study The Effect Of Lamivudine In Adult Patients Who Suffer From Chronic Hepatitis B Alone
NCT00393484	PHASE4	COMPLETED	A Study in Korea of Entecavir Versus Lamivudine in Adults With Chronic Hepatitis B Infection
NCT00403585	PHASE4	COMPLETED	Study of Adefovir Dipivoxil for Korean Patients With Chronic Hepatitis B(CHB) Who Have Completed ADF 103814
NCT00409019	PHASE4	WITHDRAWN	Trial of Telbivudine Combination Therapy vs. Continued Adefovir Monotherapy
NCT00435825	PHASE4	COMPLETED	A Study of PEGASYS (Peginterferon Alfa-2a (40KD)) in Patients With Hepatitis Be Antigen (HBeAg) Positive Chronic Hepatitis B (CHB).
NCT00436163	PHASE4	COMPLETED	A Study of Peginterferon Alfa-2a (40KD) (PEGASYS®) in Participants With Hepatitis B Envelope Antigen (HBeAg) - Positive Chronic Hepatitis B
NCT00441974	PHASE4	COMPLETED	Adefovir Dipivoxil For The Treatment Of Chinese Compensated Chronic Hepatitis B(CHB)Patients
NCT00460850	PHASE4	TERMINATED	A Study of PEGASYS (Peginterferon Alfa-2a (40KD)) in Patients With Lamivudine Resistant HBeAg-Negative Chronic Hepatitis B.
NCT00467545	PHASE4	COMPLETED	An Extension to Viral Kinetics Study of Telbivudine and Entecavir in Adults With Chronic Hepatitis B
NCT00487747	PHASE4	COMPLETED	A Study of PEGASYS (Peginterferon Alfa-2a (40KD)) in Patients With Chronic Hepatitis B.
NCT00531167	PHASE4	COMPLETED	Adding Adefovir Dipivoxil Versus Switching to Entecavir in Patients With Lamivudine-resistant Chronic Hepatitis B
NCT00537537	PHASE4	COMPLETED	To Evaluate Antiviral Efficacy of Telbivudine in Hepatitis B Antigen Positive (HbeAg-positive) Compensated Chronic Hepatitis B (CHB)
NCT00558493	PHASE4	COMPLETED	Switching Study From Lamivudine to Clevudine in the Chronic Hepatitis B Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ENTECAVIR ANHYDROUS	4	161
TENOFOVIR DISOPROXIL	4	58
TELBIVUDINE	4	37
LAMIVUDINE	4	33
TENOFOVIR ALAFENAMIDE	4	26
PEGINTERFERON ALFA-2A	4	20
ADEFOVIR DIPIVOXIL	4	17
EMTRICITABINE	4	6
PEGINTERFERON ALFA-2B	4	6
HEPATITIS B VIRUS HBSAG SURFACE PROTEIN ANTIGEN	4	3
ALBUMIN HUMAN	4	1
ALDESLEUKIN	4	1
AVATROMBOPAG	4	1
CHLORPHENIRAMINE	4	1
DIPHENHYDRAMINE	4	1
EMPAGLIFLOZIN	4	1
ETHINYL ESTRADIOL	4	1
EVOGLIPTIN	4	1
IBRUTINIB	4	1
INTERFERON ALFA-2B	4	1
LEVONORGESTREL	4	1
NITAZOXANIDE	4	1
PHYTONADIONE	4	1
PREDNISOLONE	4	1
ROPEGINTERFERON ALFA-2B	4	1
ROSUVASTATIN CALCIUM	4	1
SOFOSBUVIR	4	1
TERBINAFINE	4	1
VELPATASVIR	4	1
VITAMIN E	4	1