Low tension glaucoma

Summary

Low tension glaucoma (MONDO:0006837) is a disease with 4 cohort genes (9 GWAS associations across 2 studies) and 53 clinical trials. Top therapeutic interventions include brimonidine, timolol, and netarsudil.

At a glance

• Cohort genes: 4
• GWAS associations: 9
• Clinical trials: 53

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	low tension glaucoma
Mondo ID	MONDO:0006837
EFO	EFO:1001022
MeSH	D057066
DOID	DOID:13544
SNOMED CT	50485007
UMLS	C0152136
MedGen	56263
MedDRA	10024931
Is cancer (heuristic)	no

Also known as: glaucoma, Low tension · glaucoma, normal tension · Glaucomas, Low tension · Glaucomas, normal tension · low tension Glaucomas · normal tension glaucoma · normal tension Glaucomas · tension glaucoma, Low · tension glaucoma, normal · tension Glaucomas, Low · tension Glaucomas, normal

Data availability: 9 GWAS associations (2 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › optic nerve disorder › low tension glaucoma

Related subtypes (7): optic disk drusen, optic nerve neoplasm, optic atrophy, optic neuritis, anterior ischemic optic neuropathy, extensive peripapillary myelinated nerve fibers, isolated optic nerve aplasia

Genetics & variants

GWAS landscape

9 GWAS associations across 2 studies. Top hits map to 7 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1333037	4e-49	CDKN2B-AS1	T	1.69
rs2093210	1e-24	C14orf39	T	0.73
rs2472494	4e-13	ABCA1 - CT70	T	1.23
rs62391632	2e-11	GMDS	T	0.76
rs4657477	3e-09	TMCO1	T	0.73
rs284491	2e-08	ZFPM2	T	1.52
rs12494328	2e-08	FLNB	A	1.19
rs2041895	8e-08	TMEM263	C	1.48

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST011440	Gharahkhani P	2021	1,886	15,151	Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries.
GCST003343	Bailey JN	2016	725	11,145	Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.

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	8

MAF distribution

Bucket	Variants
common (>=0.05)	8
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	6
intergenic_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1333037	9	22040766	C>T	0.05	intron_variant	CDKN2B-AS1	4e-49	Tier 4: intronic/intergenic
rs2093210	14	60490561	C>G,T	0.05	intergenic_variant	C14orf39	1e-24	Tier 4: intronic/intergenic
rs2472494	9	104933258	T>A,C	0.05	intron_variant	ABCA1 - CT70	4e-13	Tier 4: intronic/intergenic
rs62391632	6	1957768	G>T	0.05	intron_variant	GMDS	2e-11	Tier 4: intronic/intergenic
rs4657477	1	165766938	C>G,T	0.05	intron_variant	TMCO1	3e-09	Tier 4: intronic/intergenic
rs284491	8	104946405	C>T	0.05	intergenic_variant	ZFPM2	2e-08	Tier 4: intronic/intergenic
rs12494328	3	58049770	G>A	0.05	intron_variant	FLNB	2e-08	Tier 4: intronic/intergenic
rs2041895	12	106956310	C>A,G,T	0.05	intron_variant	TMEM263	8e-08	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
C14orf39	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
FLNB	Orphanet:1190	Atelosteogenesis type I
FLNB	Orphanet:1263	Boomerang dysplasia
FLNB	Orphanet:3275	Spondylocarpotarsal synostosis
FLNB	Orphanet:503	Larsen syndrome
FLNB	Orphanet:56305	Atelosteogenesis type III

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
C14orf39	HGNC:19849	ENSG00000179008	Q8N1H7	Protein SIX6OS1	gwas
CDKN2B-AS1	HGNC:34341	ENSG00000240498		CDKN2B and CDKN2A antisense cis and trans regulatory RNA 1	gwas
FLNB	HGNC:3755	ENSG00000136068	O75369	Filamin-B	gwas
GMDS	HGNC:4369	ENSG00000112699	O60547	GDP-mannose 4,6 dehydratase	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
C14orf39	Protein SIX6OS1	Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination.
FLNB	Filamin-B	Connects cell membrane constituents to the actin cytoskeleton.
GMDS	GDP-mannose 4,6 dehydratase	Catalyzes the conversion of GDP-D-mannose to GDP-4-dehydro-6-deoxy-D-mannose.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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	1	7.3×	0.390
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
C14orf39	Other/Unknown	no		SIX6OS1
CDKN2B-AS1	Other/Unknown	no
FLNB	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
GMDS	Enzyme (other)	yes	4.2.1.47	GDP_Man_deHydtase, NAD(P)-bd_dom, NAD(P)-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	3
transverse colon	2
adenohypophysis	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
rectum	1
tibial nerve	1
lower esophagus mucosa	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
C14orf39	129	broad	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
CDKN2B-AS1	169	ubiquitous	marker	mucosa of transverse colon, rectum, transverse colon
FLNB	290	ubiquitous	marker	mucosa of transverse colon, tibial nerve, transverse colon
GMDS	264	ubiquitous	marker	parotid gland, mucosa of transverse colon, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNB	2,927
GMDS	1,450
C14orf39	478
CDKN2B-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNB	O75369	23
GMDS	O60547	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C14orf39	Q8N1H7	58.97

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 4 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
GDP-fucose biosynthesis	1	951.7×	0.002	GMDS
ISG15 antiviral mechanism	1	75.1×	0.013	FLNB

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
meiotic DNA double-strand break processing involved in reciprocal meiotic recombination	1	1872.4×	0.004	C14orf39
‘de novo’ GDP-L-fucose biosynthetic process	1	1872.4×	0.004	GMDS
GDP-L-fucose biosynthetic process	1	1404.3×	0.004	GMDS
GDP-mannose metabolic process	1	936.2×	0.004	GMDS
keratinocyte development	1	510.7×	0.005	FLNB
obsolete regulation of DNA-binding transcription factor activity	1	510.7×	0.005	C14orf39
epithelial cell morphogenesis	1	312.1×	0.007	FLNB
synaptonemal complex assembly	1	216.1×	0.009	C14orf39
homologous chromosome pairing at meiosis	1	200.6×	0.009	C14orf39
oogenesis	1	127.7×	0.013	C14orf39
skeletal muscle tissue development	1	96.8×	0.015	FLNB
cellular response to type II interferon	1	69.3×	0.019	FLNB
Notch signaling pathway	1	47.2×	0.026	GMDS
actin cytoskeleton organization	1	26.4×	0.043	FLNB
spermatogenesis	1	11.7×	0.088	C14orf39
signal transduction	1	5.3×	0.176	FLNB

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): AMA0076.

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GMDS	1	2
C14orf39	0	0
CDKN2B-AS1	0	0
FLNB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	GMDS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GMDS	8	Binding:8
FLNB	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GMDS	4.2.1.47	GDP-mannose 4,6-dehydratase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	GMDS

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	1	GMDS
C	Druggable family + PDB, no drug	1	FLNB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	C14orf39, CDKN2B-AS1

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)
C14orf39	0	—
CDKN2B-AS1	0	—
FLNB	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 53.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	41
PHASE4	7
PHASE2	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01446497	PHASE4	UNKNOWN	Efficacy and Safety Study of Combigan and 0.5% Timoptic in Normal Tension Glaucoma
NCT01995136	PHASE4	COMPLETED	Investigation of Intraocular Pressure (IOP) Reduction Efficacy of Travoprost Ophthalmic Solution in Patients With Normal Tension Glaucoma
NCT02863705	PHASE4	COMPLETED	Efficacy and Safety of COMBIGAN® in Korean Patients With Primary Open Angle Glaucoma (POAG) and Normal Tension Glaucoma (NTG)
NCT03323164	PHASE4	COMPLETED	Peripapillary Blood Flow After Use of Anti-glaucoma Medications: An OCT Angiography Study
NCT04981886	PHASE4	UNKNOWN	Intraocular Pressure Reduction Efficacy of Rhopressa and Lumigan in Normal Tension Glaucoma
NCT05279716	PHASE4	UNKNOWN	Study in Prostaglandin Associated Peri-orbitopathy Switching From Prostaglandin Monotherapy to Omidenepag Isopropyl
NCT06449352	PHASE4	COMPLETED	Effect of Netarsudil vs Brimonidine in NTG Patients on Latanoprost
NCT07354477	PHASE2	RECRUITING	Single-site Pilot Study Evaluating the Effect of QLS-111 Ophthalmic Solution on Posterior Perfusion and Vessel Dilation
NCT01864317	PHASE2	TERMINATED	Assessment of Optic Nerve Radiation in Patients With Glaucoma and Ocular Hypertension by 7 Tesla Diffusion Tensor Imaging
NCT03106532	PHASE2	COMPLETED	Evaluation of PHP-201 Ophthalmic Solution in Patients With Normal Tension Glaucoma
NCT04857827	PHASE2	COMPLETED	A Study to Evaluate Safety and Tolerability of QLS-101 in NTG
NCT06030193	PHASE2	COMPLETED	Study of an Investigational Product, QLS-111, Provided as an Eyedrop, for Treatment of Normal Tension Glaucoma (NTG)
NCT02959242	Not specified	RECRUITING	Dresden Glaucoma and Treatment Study (DGTS)
NCT03870230	Not specified	RECRUITING	Investigation of Neurovascular Coupling in Glaucoma Patients and Healthy Subjects
NCT04651530	Not specified	RECRUITING	Endoscopic Cyclophotocoagulation in Normal Tension Glaucoma
NCT05371977	Not specified	RECRUITING	Deep Sclerectomy Versus Trabeculectomy in Normal Tension Glaucoma
NCT05902871	Not specified	ACTIVE_NOT_RECRUITING	Direct Selective Laser Trabeculoplasty in Ethnic Chinese Population
NCT06023927	Not specified	NOT_YET_RECRUITING	Obstructive Sleep Apnea as a Risk Factor for Normal Tension Glaucoma and a Crucial Step in Preventing Blindness
NCT06443411	Not specified	ENROLLING_BY_INVITATION	R&D of Non-invasive Innovative Intracranial Waves Monitoring System for Diagnostics and Treatment Monitoring of Patients with Normal Tension Glaucoma
NCT06682962	Not specified	RECRUITING	Transcorneal Electrical Stimulation for the Treatment of Visual Field Defects in Patients With Open-Angle Glaucoma
NCT07075887	Not specified	NOT_YET_RECRUITING	Optic Nerve Head Evaluation Through Multimodal Blood Flow Analysis: a Prospective Observational, Multi-center Study
NCT07300852	Not specified	NOT_YET_RECRUITING	DSLT in Normal Tension Glaucoma (NTG) Asian Eyes
NCT00175786	Not specified	COMPLETED	Magnetic Resonance Imaging of Patients With Normal Tension Glaucoma
NCT00570362	Not specified	COMPLETED	Systemic Glutathione Level in Normal Tension Glaucoma
NCT00706056	Not specified	COMPLETED	A New View of Normal Tension Glaucoma: Autoregulation and Systemic Blood Pressure
NCT00739154	Not specified	UNKNOWN	Protective Effect of Phenytoin on Glaucoma
NCT01175902	Not specified	COMPLETED	Intraocular Pressure and Ocular Perfusion Pressure of Cosopt in Normal Tension Glaucoma
NCT01192061	Not specified	COMPLETED	Autonomic Nervous System Activity and Normal Tension Glaucoma
NCT01209624	Not specified	COMPLETED	Observational Study of the Long-term Effect of Latanoprost in Normal Tension Glaucoma
NCT01254149	Not specified	COMPLETED	IOP Lowering Effects of Topical Anesthetics Used Frequently in the Ophthalmology Clinic
NCT01391247	Not specified	COMPLETED	Validation of Retinal Oximetry in Glaucoma Patients: a Structural and Functional Correlation
NCT01487655	Not specified	COMPLETED	Waveform Analysis of the Doppler Curve of Ophthalmic Arteries in Glaucoma Patients
NCT01488032	Not specified	COMPLETED	Differences in Nerve Fiber Layer Between Patients With Normal- and High-Pressure-Glaucoma
NCT01769521	Not specified	COMPLETED	Relationship Between 24-hour IOP Pattern and the 24-hour Blood Pressure Pattern in Patients With POAG
NCT01794442	Not specified	UNKNOWN	Study on the Oxygen Saturation in Pulsating and Non-pulsating Central Retinal Veins
NCT01795014	Not specified	UNKNOWN	Correlation of Orbital Cerebrospinal Fluid Pressure and Retinal Venous Outflow in Primary Open-angle Glaucoma
NCT01802463	Not specified	COMPLETED	Study on Ocular Blood Flow and the Orbital Cerebrospinal Fluid Pressure in Glaucoma
NCT01840202	Not specified	COMPLETED	Ocular Blood Flow in Glaucoma Patients - the Leuven Eye Study
NCT01862627	Not specified	COMPLETED	Macular Retinoschisis and Detachment Associated With Glaucomatous Optic Neuropathy
NCT01912599	Not specified	COMPLETED	Pilot Study on Ambulatory Intraocular Pressure and Blood Pressure Monitoring in Glaucoma

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BRIMONIDINE	4	10
TIMOLOL	4	7
NETARSUDIL	4	2
BIMATOPROST	4	1
DORZOLAMIDE	4	1
AMA0076	3	1
CHEMBL1744069	0	2
CHEMBL4303730	0	1