Portal hypertension

Summary

Portal hypertension (MONDO:0005080) is a disease with 3 cohort genes (8 GWAS associations across 9 studies) and 230 clinical trials. Top therapeutic interventions include propranolol, carvedilol, and entecavir anhydrous.

At a glance

• Cohort genes: 3
• GWAS associations: 8
• ClinVar variants: 5
• Clinical trials: 230

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	portal hypertension
Mondo ID	MONDO:0005080
EFO	EFO:0000666
MeSH	D006975
DOID	DOID:10762
ICD-10-CM	K76.6
ICD-11	1506184775
NCIT	C3119
SNOMED CT	34742003
UMLS	C0020541
MedGen	9375
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants · 8 GWAS associations (9 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › hepatic vascular disorder › portal hypertension

Related subtypes (10): portal vein thrombosis, hepatic infarction, nutmeg liver, liver angiosarcoma, peliosis hepatis, hepatic vein thrombosis, Budd-Chiari syndrome, hepatic veno-occlusive disease, portosinusoidal vascular disease, Fontan-associated liver disease

Genetics & variants

GWAS landscape

8 GWAS associations across 9 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
rs738408	2e-93	PNPLA3	C	0.52
rs3747207	3e-79	PNPLA3	G	0.57
rs72999033	1e-20	HAPLN4	C	0.44
rs17217098	7e-17	PBX4	G	0.41
rs738409	2e-15	PNPLA3	?	1.65
rs532403614	2e-12	MAPT-AS1	C	2.39
rs543006888	1e-11	EPHA7	T	2.85
rs369517031	4e-11	TRPC4AP	G	3.69

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90476089	Verma A	2024	2,905	445,920	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90080289	Backman JD	2021	753	387,177	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90084275	Backman JD	2021	753	387,177	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90478455	Verma A	2024	547	58,958	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436373	Zhou W	2018	529	400,055	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90480339	Verma A	2024	445	120,837	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90482174	Verma A	2024	445	120,837	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90727248	Kim HI	2026	157	43,869	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.
GCST90837535	Koyama S	2025	0	0	Genetics and context for precision health in Greater Boston.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	6

MAF distribution

Bucket	Variants
common (>=0.05)	4
low_freq (0.01-0.05)	1
rare (<0.01)	3
unknown	0

Functional consequences

Consequence	Count
intron_variant	5
synonymous_variant	1
3_prime_UTR_variant	1
missense_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs738408	22	43928850	C>A,G,T	0.224	synonymous_variant	PNPLA3	2e-93	Tier 4: intronic/intergenic
rs3747207	22	43928975	G>A,C,T	0.218	intron_variant	PNPLA3	3e-79	Tier 4: intronic/intergenic
rs72999033	19	19255823	C>T	0.049	3_prime_UTR_variant	HAPLN4	1e-20	Tier 2: splice/UTR
rs17217098	19	19591575	G>A	0.064	intron_variant	PBX4	7e-17	Tier 4: intronic/intergenic
rs738409	22	43928847	C>A,G,T	0.05	missense_variant	PNPLA3	2e-15	Tier 1: coding
rs532403614	17	45869481	C>T	0.001	intron_variant	MAPT-AS1	2e-12	Tier 4: intronic/intergenic
rs543006888	6	93295443	T>C	0.001	intron_variant	EPHA7	1e-11	Tier 4: intronic/intergenic
rs369517031	20	35021143	G>A	0	intron_variant	TRPC4AP	4e-11	Tier 4: intronic/intergenic

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

3 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3384060	NM_080916.3(DGUOK):c.760GAT[1] (p.Asp255del)	DGUOK	Pathogenic	criteria provided, single submitter
1344845	NM_018384.5(GIMAP5):c.667C>T (p.Leu223Phe)	GIMAP1-GIMAP5	Pathogenic/Likely pathogenic	no assertion criteria provided
1344846	NM_018384.5(GIMAP5):c.326C>T (p.Pro109Leu)	GIMAP1-GIMAP5	Pathogenic/Likely pathogenic	no assertion criteria provided
1344844	NM_018384.5(GIMAP5):c.140T>C (p.Ile47Thr)	GIMAP5	Pathogenic/Likely pathogenic	no assertion criteria provided
1188820	NM_018384.5(GIMAP5):c.611T>C (p.Leu204Pro)	GIMAP1-GIMAP5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DGUOK	Orphanet:279934	Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency
DGUOK	Orphanet:329314	Adult-onset multiple mitochondrial DNA deletion syndrome due to DGUOK deficiency

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GIMAP5	HGNC:18005	ENSG00000196329	Q96F15	GTPase IMAP family member 5	clinvar
DGUOK	HGNC:2858	ENSG00000114956	Q16854	Deoxyguanosine kinase, mitochondrial	clinvar
GIMAP1-GIMAP5	HGNC:51257	ENSG00000281887		GIMAP1-GIMAP5 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GIMAP5	GTPase IMAP family member 5	Plays a role in T lymphocyte development and the optimal generation of CD4/CD8 double-positive thymocytes.
DGUOK	Deoxyguanosine kinase, mitochondrial	Phosphorylates deoxyguanosine and deoxyadenosine in the mitochondrial matrix, with the highest efficiency for deoxyguanosine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GIMAP5	Other/Unknown	no		G_AIG1, P-loop_NTPase, GIMA/IAN/Toc
DGUOK	Kinase	yes	2.7.1.113	DCK/DGK, P-loop_NTPase, DNK_dom
GIMAP1-GIMAP5	Other/Unknown	no

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
granulocyte	2
right lung	1
upper lobe of left lung	1
adenohypophysis	1
olfactory segment of nasal mucosa	1
pituitary gland	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GIMAP5	165	broad	marker	right lung, granulocyte, upper lobe of left lung
DGUOK	297	ubiquitous	marker	adenohypophysis, olfactory segment of nasal mucosa, pituitary gland
GIMAP1-GIMAP5	126		marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GIMAP5	1,560
DGUOK	201
GIMAP1-GIMAP5	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GIMAP5	Q96F15	1
DGUOK	Q16854	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Purine salvage	1	878.5×	0.001	DGUOK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
guanosine metabolic process	1	16852.0×	1e-04	DGUOK
dGTP metabolic process	1	16852.0×	1e-04	DGUOK
purine deoxyribonucleoside metabolic process	1	16852.0×	1e-04	DGUOK
dAMP salvage	1	5617.3×	3e-04	DGUOK
mitochondrial ATP synthesis coupled electron transport	1	1872.4×	6e-04	DGUOK
negative regulation of neuron projection development	1	237.3×	0.004	DGUOK

Therapeutics

Drugs indicated for this disease

0 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Carvedilol	Phase 3 (in late-stage trials)
Propranolol	Phase 3 (in late-stage trials)
Simvastatin	Phase 3 (in late-stage trials)
Somatostatin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Empagliflozin, Perflubutane, Sapropterin, Sorafenib, Sulfur Hexafluoride.

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GIMAP5	0	0
DGUOK	0	0
GIMAP1-GIMAP5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DGUOK	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DGUOK	2.7.1.113	deoxyguanosine kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	DGUOK
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	GIMAP5, GIMAP1-GIMAP5

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)
GIMAP5	0	—
DGUOK	1	—
GIMAP1-GIMAP5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 230.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	170
PHASE4	21
PHASE2	14
PHASE3	13
PHASE2/PHASE3	6
PHASE1/PHASE2	4
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04073290	PHASE4	RECRUITING	Prevention of Post-TIPS Hepatic Encephalopathy by Administration of Rifaximin and Lactulose
NCT05872698	PHASE4	ACTIVE_NOT_RECRUITING	Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of Oesophageal Varices Trial.
NCT06449339	PHASE4	RECRUITING	Non-selective Beta-blocker in Compensated Advanced Chronic Liver Disease
NCT07521332	PHASE4	RECRUITING	Apixaban-PK Trial: Preventing Portal Hypertension Complications in Cirrhosis
NCT00332904	PHASE4	UNKNOWN	Effect of Betablocker or Aldosterone Antagonist Therapy on Patients With Liver Cirrhosis
NCT00369694	PHASE4	COMPLETED	Short Course Terlipressin for Control of Acute Variceal Bleeding
NCT00414713	PHASE4	UNKNOWN	Transfusion Requirements in Gastrointestinal (GI) Bleeding
NCT00450164	PHASE4	COMPLETED	Secondary Prophylaxis After Variceal Bleeding in Non-Responders
NCT00534677	PHASE4	COMPLETED	The Safety & Efficacy of Terlipressin vs Octreotide for the Control of Variceal Bleed
NCT00563602	PHASE4	UNKNOWN	Treatment for Prevention of Variceal Rebleeding Guided by the Hemodynamic Response
NCT00570622	PHASE4	COMPLETED	Effect of Pioglitazone on Portal and Systemic Hemodynamics in Patients With Advanced Cirrhosis
NCT01070641	PHASE4	UNKNOWN	RCT of Carvedilol Versus Variceal Band Ligation in the Primary Prophylaxis of Oesophageal Variceal Haemorrhage
NCT01842113	PHASE4	TERMINATED	Quality of Life and Nutritional Improvements in Cirrhotic Patients
NCT02344719	PHASE4	COMPLETED	Effect of Taurine on Portal Hemodynamics in Patients With Advanced Liver Cirrhosis
NCT02489045	PHASE4	COMPLETED	Noninvasive Subharmonic Aided Pressure Estimation of Portal Hypertension
NCT02907749	PHASE4	COMPLETED	Spironolactone on Fibrosis Progrssion-Portal Hypertension(FP-PH)in Cirrhosis
NCT02925975	PHASE4	UNKNOWN	Early Precise Diagnosis and Intervention of CPT Based on a Noninvasive 3D-vHPS
NCT02945956	PHASE4	UNKNOWN	Treatment of Low-grade Cirrhotic Portal Hypertension Due to Hepatitis B Virus With Fuzheng Huayu and Entecavir
NCT02945982	PHASE4	UNKNOWN	Treatment of Moderate and Severe Cirrhotic Portal Hypertension Due to HBV With Fuzheng Huayu and Entecavir
NCT02994485	PHASE4	COMPLETED	Evaluation Of The Portal Pressure By Doppler Ultrasound In Cirrhotic Patients Before And After Simvastatin
NCT04107428	PHASE4	UNKNOWN	Somatostatin in Living Donor Liver Transplantation
NCT05470205	PHASE3	RECRUITING	Noninvasive Subharmonic Aided Pressure Estimation of Portal Hypertension; Renewal
NCT06434753	PHASE3	RECRUITING	Zinc Supplementation to Improve Prognosis in Patients With Compensated Advanced Chronic Liver Disease.
NCT00006398	PHASE3	COMPLETED	Prevention of Esophageal Varices by Beta-Adrenergic Blockers
NCT00331188	PHASE3	COMPLETED	Use of Sanvar® With Endoscopic Treatment for the Control of Acute Variceal Bleeding
NCT00493480	PHASE3	COMPLETED	Danish Carvedilol Study in Portal Hypertension
NCT00787436	PHASE3	WITHDRAWN	Secondary Prophylaxis of Gastrointestinal Bleeding in Cirrhotic Patients Using THALIDOMIDE
NCT01131962	PHASE3	COMPLETED	Comparing Two Methods to Stop Vomiting of Blood Using the Endoscope
NCT01440829	PHASE2/PHASE3	COMPLETED	The Effectiveness of L-ornithine-L-aspartate (LOLA) on Plasma Ammonia in Cirrhotic Patients After TIPS
NCT01456286	PHASE2/PHASE3	COMPLETED	Randomized Controlled Trial to Assess the Effects of Sapropterin on Hepatic and Systemic Hemodynamics in Patients With Liver Cirrhosis and Portal Hypertension
NCT01560845	PHASE2/PHASE3	UNKNOWN	ABMSC Infusion Through Hepatic Artery in Portal Hypertension Surgery for the Treatment of Liver Cirrhosis
NCT01897051	PHASE2/PHASE3	UNKNOWN	Rifaximin and Propranolol Combination Therapy Versus Propranolol Monotherapy in Cirrhotic Patients
NCT02134626	PHASE3	COMPLETED	Simvastatin Effect on Portal Hypertension
NCT02508623	PHASE3	UNKNOWN	Effect of Administration of Rifaximin on the Portal Pressure of Patients With Liver Cirrhosis and Esophageal Varices
NCT02975323	PHASE3	UNKNOWN	Doppler Ultrasound Hepatic Vein Waveform as a Non-invasive Tool in the Assessment of Severity of Portal Hypertension
NCT03720067	PHASE2/PHASE3	UNKNOWN	Propranolol, Carvedilol and Rosuvastatin in the Prevention of Variceal Bleeding in Cirrhotic Portal Hypertension
NCT04010669	PHASE3	UNKNOWN	The Role of Somatostatin in the Hemodynamics of the Hepatic Circulation in Patients Undergoing Liver Resection
NCT05227833	PHASE3	COMPLETED	Vonoprazan Efficacy to Prevent Post Variceal Band Ligation Ulcer
NCT05794555	PHASE3	COMPLETED	LiveSMART Trial to Prevent Falls in Patients With Cirrhosis
NCT06000748	PHASE2/PHASE3	TERMINATED	NEPH-ROSIS (NEPHrology in CirRhOSIS) Pilot Trial: A Trial to Treat Acute Kidney Injury Among Hospitalized Cirrhosis Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PROPRANOLOL	4	12
CARVEDILOL	4	10
ENTECAVIR ANHYDROUS	4	6
LACTULOSE	4	4
RIFAXIMIN	4	4
TERLIPRESSIN	4	4
PRAZOSIN	4	3
TIMOLOL	4	3
SAPROPTERIN	4	2
SPIRONOLACTONE	4	2
AMBRISENTAN	4	1
APIXABAN	4	1
BULEVIRTIDE	4	1
ETHIODIZED OIL	4	1
ISOSORBIDE	4	1
ISOSORBIDE MONONITRATE	4	1
IVABRADINE	4	1
NADOLOL	4	1
NORFLOXACIN	4	1
OCTREOTIDE	4	1
PANTOPRAZOLE	4	1
PIOGLITAZONE	4	1
POLIDOCANOL	4	1
SIMVASTATIN	4	1
SULFUR HEXAFLUORIDE	4	1
THALIDOMIDE	4	1
SOMATOSTATIN	3	5
MECRYLATE	3	1
ZINC ACEXAMATE	3	1
DEXPROPRANOLOL	2	4