LTA

Summary

LTA (lymphotoxin alpha, HGNC:6709) is a protein-coding gene on chromosome 6p21.33, encoding Lymphotoxin-alpha (P01374). Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM.

The encoded protein, a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. The protein is highly inducible, secreted, and forms heterotrimers with lymphotoxin-beta which anchor lymphotoxin-alpha to the cell surface. This protein also mediates a large variety of inflammatory, immunostimulatory, and antiviral responses, is involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis. Genetic variations in this gene are associated with susceptibility to leprosy type 4, myocardial infarction, non-Hodgkin’s lymphoma, and psoriatic arthritis. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 4049 — RefSeq curated summary.

At a glance

• GWAS associations: 38
• Clinical variants (ClinVar): 16 total
• Druggable target: yes
• MANE Select transcript: NM_000595

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6709
Approved symbol	LTA
Name	lymphotoxin alpha
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	TNFSF1, LT
Ensembl gene	ENSG00000226979
Ensembl biotype	protein_coding
OMIM	153440
Entrez	4049

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 retained_intron

ENST00000418386, ENST00000454783, ENST00000471842, ENST00000489638, ENST00000877327

RefSeq mRNA: 2 — MANE Select: NM_000595 NM_000595, NM_001159740

CCDS: CCDS4701

Canonical transcript exons

ENST00000383304 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 119 present calls, max score 82.94.

FANTOM5 (CAGE): breadth broad, TPM avg 30.8199 / max 6429.4078, expressed in 222 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66904	28.5886	185
66903	1.0406	130
66907	0.4113	86
66906	0.1779	36
66911	0.1666	39
66905	0.1506	56
66909	0.0941	37
66908	0.0589	32
66910	0.0450	28
66913	0.0434	22

Top tissues by expression

129 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.94	gold quality
granulocyte	CL:0000094	81.45	gold quality
lymph node	UBERON:0000029	81.25	gold quality
blood	UBERON:0000178	76.34	gold quality
vermiform appendix	UBERON:0001154	74.82	gold quality
spleen	UBERON:0002106	73.73	gold quality
right testis	UBERON:0004534	66.45	gold quality
left testis	UBERON:0004533	65.65	gold quality
testis	UBERON:0000473	64.87	gold quality
leukocyte	CL:0000738	62.88	gold quality
tonsil	UBERON:0002372	62.41	gold quality
bone marrow	UBERON:0002371	62.35	gold quality
monocyte	CL:0000576	61.11	gold quality
duodenum	UBERON:0002114	60.90	gold quality
rectum	UBERON:0001052	57.37	gold quality
cerebellum	UBERON:0002037	55.13	gold quality
cerebellar cortex	UBERON:0002129	55.06	gold quality
cerebellar hemisphere	UBERON:0002245	55.06	gold quality
small intestine Peyer’s patch	UBERON:0003454	55.05	gold quality
small intestine	UBERON:0002108	54.97	gold quality
bone marrow cell	CL:0002092	54.92	gold quality
right hemisphere of cerebellum	UBERON:0014890	53.45	gold quality
mucosa of transverse colon	UBERON:0004991	53.35	gold quality
gastrocnemius	UBERON:0001388	52.81	gold quality
placenta	UBERON:0001987	51.62	gold quality
gall bladder	UBERON:0002110	51.14	gold quality
smooth muscle tissue	UBERON:0001135	50.65	gold quality
muscle of leg	UBERON:0001383	50.61	gold quality
colonic epithelium	UBERON:0000397	50.35	gold quality
nucleus accumbens	UBERON:0001882	49.88	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-8530	yes	112.03
E-HCAD-29	no	248.51
E-ANND-3	no	0.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, JUN, MSC, MYC, NFKB1, NFKB2, NFKB, REL, RELA, SALL4, SP1, STAT4, STAT5A, TCF3, TFAP2A, TFAP4, TP53

miRNA regulators (miRDB)

47 targeting LTA, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-6792-3P	98.41	66.86	1359

Literature-anchored findings (GeneRIF, showing 38)

• TNFB*G allele plays some role in the tumorigenesis or activation of dormant tumour cells in breast cancer (PMID:11841482)
• Genetic variation in LTalpha production is unlikely to play a major role in risk of cutaneous malignant melanoma. (PMID:11841484)
• One hundred sixty-four unrelated healthy individuals from Chinese Han population were investigated in order to define the distribution of eight polymorphic loci within the tumor necrosis factor (TNF) gene cluster (PMID:11924527)
• analysis of the role of the TNFB gene in genetic susceptibility to juvenile idiopathic arthritis (PMID:11975986)
• Single-nucleotide polymorphisms in the lymphotoxin-alpha gene are associated with susceptibility to myocardial infarction. (PMID:12426569)
• the MHC contains genetic elements outside the LTA-TNF region that modify the effect of HLA-DRB1 on susceptibility to rheumatoid arthritis (PMID:12528108)
• TNFB haplotypes modify susceptibility to type I diabetes mellitus independently of HLA class II in a Moroccan population (PMID:12622777)
• TNFB polymorphism may confer susceptibility to schizophrenia in the Korean population. (PMID:12648734)
• Polymorphism of this protein is asociated with acute biliary pancreatitis. (PMID:12679941)
• Polymorphisms of the TNFB gene may contribute to a predisposition to psoriasis in the Korean population. (PMID:12709814)
• analysis of the association of NcoI polymorphism within the promoter/enhancer region of TNFalpha and the first intron of TNFbeta encoding gene with toxic complications following sten cell transplantation (PMID:12953135)
• We investigated two genetic polymorphisms in the TNF locus (TNF-alpha -308 G–>A and TNF-beta +252 A–>G) as risk factors for cerebral infarction (CI) by determining its prevalence in 294 survivors of CI, and in 581 age, gender, and race-matched controls (PMID:14593215)
• nucleotide polymorphisms in TNF-beta (A/A allele), may affect the natural course of hepatitis C virus infection, in particular, the disease progression. (PMID:14635012)
• In transplanted murine tumors human lymphotoxin alpha functions as a key cytokine, inducing signals that lead to lymphoid neo-organogenesis even in the absence of functional B and T cells. (PMID:15034015)
• expression may be genetically regulated by allele-specific recruitment of the transcriptional repressor ABF-1 (PMID:15052269)
• The AA genotype of LT-alpha+250 is associated with the development of chorioamnionitis among premature births (PMID:15128916)
• lymphotoxin-alpha binds to galectin-2, a member of the galactose-binding lectin family; link between the LTA cascade and the pathogenesis of myocardial infarction (PMID:15129282)
• Presence of TNFB*A329G polymorphism in addition to APOE*E4 variant is associated with significantly higher releases of interleukin 8 and tumor necrosis factor alpha, prolonged intubation, and increased transfusion. (PMID:15224026)
• CRP levels are influenced not only by environmental factors but also by the polymorphism of LTA or other genes in the same haplotype block. (PMID:15306179)
• TNF/LTA genotypes might play an opposite role in the pathogenesis of gastric cancer and duodenal ulcer. (PMID:15381184)
• Genetic variation in the HLA-DRB1 and LTA-TNF regions is associated with treatment response of early RA to methotrexate or etanercept. (PMID:15457442)
• We identified an association between psoriatic arthritis and one of the microsatellite markers within the TNFB locus at the HLA region on chromosome 6. (PMID:15517637)
• Single-nucleotide polymorphisms of the lymphotoxin alpha gene were not associated with essential hypertension. (PMID:15533732)
• Single nucleotide polymorphisms of lymphotoxin-alpha is associated with Lofgren’s syndrome in Czech patients with sarcoidosis (PMID:15713215)
• functional T60N variant of LTA is associated with type 2 diabetes and other features of the metabolic syndrome among Danish Caucasian individuals. (PMID:15729581)
• TNF-beta polymorphism may modify individual susceptibility to breast cancer in premenopausal Korean women (PMID:15803361)
• Genetic variations in these proinflammatory mediators and their receptors appear to influence the susceptibility and severity of the inflammatory response within the eyes of patients during the development of IAU(idiopathic acute anterior uveitis). (PMID:15851552)
• Genome-wide association studies identified significant association for myocardiaI infarction with the LTA gene (encoding lymphotoxin-alpha) (PMID:15861005)
• LTA(IVS1-82)C variant constituent of the GAC haplotype, was associated with increased risk of spontaneous preterm birth. (PMID:15951664)
• HBXIP up-regulates LTA expression in hepatocytes. (PMID:15955450)
• Evidence of an association between lymphotoxin alpha genotype and the extent of coronary atherosclerosis is provided. (PMID:15973460)
• It is unlikely that the TNF -308 or LTA NcoI polymorphisms influence asthma susceptibility individually, but that this haplotype of variants may be functional or may be in linkage disequilibrium with other functional single-nucleotide polymorphisms. (PMID:15976383)
• TNFalpha/TGFbeta combination as well as M. leprae infection triggered an increase in the apoptosis rate in the cultured Schwann cells. (PMID:16215460)
• No correlation was found between the TNF-beta+252 polymorphism and irritable bowel syndrome. (PMID:16246225)
• IL-10, but not TNF-alpha, TNF-beta, or IL-6 polymorphisms are associated with lung cancer (PMID:16276011)
• Authors could not confirm an association between the LTA locus and clinical or biological response to infliximab in a large cohort of CD patients. (PMID:16609369)
• The LTA 252A/G polymorphism is moderately associated with sub-clinical atherosclerosis. (PMID:16874159)
• A polymorphism of the TNF gene is associated with a susceptibility to bladder cancer and its disease status. (PMID:16882065)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnfa	ENSDARG00000009511
danio_rerio	tnfb	ENSDARG00000013598
mus_musculus	Lta	ENSMUSG00000024402
rattus_norvegicus	Lta	ENSRNOG00000000838

Paralogs (8): CD40LG (ENSG00000102245), FASLG (ENSG00000117560), TNFSF11 (ENSG00000120659), TNFSF10 (ENSG00000121858), TNFSF14 (ENSG00000125735), TNFSF15 (ENSG00000181634), LTB (ENSG00000227507), TNF (ENSG00000232810)

Protein

Protein identifiers

Lymphotoxin-alpha — P01374 (reviewed: P01374)

Alternative names: TNF-beta, Tumor necrosis factor ligand superfamily member 1

All UniProt accessions (2): P01374, Q5STV3

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that in its homotrimeric form binds to TNFRSF1A/TNFR1, TNFRSF1B/TNFBR and TNFRSF14/HVEM. In its heterotrimeric form with LTB binds to TNFRSF3/LTBR. Lymphotoxin is produced by lymphocytes and is cytotoxic for a wide range of tumor cells in vitro and in vivo.

Subunit / interactions. Homotrimer, and heterotrimer of either two LTB and one LTA subunits or (less prevalent) two LTA and one LTB subunits. Interacts with TNFRSF14.

Subcellular location. Secreted. Membrane.

Disease relevance. Psoriatic arthritis (PSORAS) [MIM:607507] An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). Disease susceptibility is associated with variants affecting the gene represented in this entry.

Polymorphism. A polymorphism in LTA accounts, in part, for susceptibility to leprosy linked to chromosome 6p21.3 (LPRS4) [MIM:610988].

Similarity. Belongs to the tumor necrosis factor family.

RefSeq proteins (2): NP_000586, NP_001153212 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002960	TNF_beta	Family
IPR006052	TNF_dom	Domain
IPR006053	TNF	Family
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR021184	TNF_CS	Conserved_site

Pfam: PF00229

UniProt features (26 total): strand 12, sequence variant 4, turn 2, helix 2, glycosylation site 2, signal peptide 1, chain 1, domain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1TNR	X-RAY DIFFRACTION	2.85
4MXV	X-RAY DIFFRACTION	3.2
4MXW	X-RAY DIFFRACTION	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01374-F1	83.96	0.68

Antibody-complex structures (SAbDab): 2 — 4MXV, 4MXW

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (2): 41, 96

Mutagenesis-validated functional residues (1):

Position	Phenotype
142	reduces binding of lta(1)-ltb(2) to ltbr and ltbr-mediated nf-kappa-b signaling activation. reduces binding of lta(1)-lt

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway
R-HSA-5669034	TNFs bind their physiological receptors
R-HSA-5676594	TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway

MSigDB gene sets: 382 (showing top): GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, MODULE_64, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_ACTIVATION_OF_NF_KAPPAB_INDUCING_KINASE_ACTIVITY, GOBP_LYMPH_NODE_DEVELOPMENT, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_NEUROGENESIS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (22): response to hypoxia (GO:0001666), positive regulation of chronic inflammatory response to antigenic stimulus (GO:0002876), positive regulation of humoral immune response mediated by circulating immunoglobulin (GO:0002925), apoptotic process (GO:0006915), immune response (GO:0006955), humoral immune response (GO:0006959), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), cell-cell signaling (GO:0007267), response to nutrient (GO:0007584), response to xenobiotic stimulus (GO:0009410), response to lipopolysaccharide (GO:0032496), positive regulation of type II interferon production (GO:0032729), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of fibroblast proliferation (GO:0048147), lymph node development (GO:0048535), defense response to Gram-positive bacterium (GO:0050830), positive regulation of glial cell proliferation (GO:0060252), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), cell communication (GO:0007154), signaling (GO:0023052), positive regulation of apoptotic process (GO:0043065)

GO Molecular Function (4): signaling receptor binding (GO:0005102), cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	2
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	2
cellular process	2
signaling	2
response to chemical	2
cellular anatomical structure	2
response to stress	1
response to decreased oxygen levels	1
chronic inflammatory response to antigenic stimulus	1
positive regulation of chronic inflammatory response	1
positive regulation of inflammatory response to antigenic stimulus	1
regulation of chronic inflammatory response to antigenic stimulus	1
humoral immune response mediated by circulating immunoglobulin	1
positive regulation of immunoglobulin mediated immune response	1
positive regulation of humoral immune response	1
regulation of humoral immune response mediated by circulating immunoglobulin	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
immune system process	1
response to stimulus	1
immune response	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
response to nutrient levels	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
positive regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
negative regulation of cell population proliferation	1
fibroblast proliferation	1
regulation of fibroblast proliferation	1
hematopoietic or lymphoid organ development	1
defense response to bacterium	1
positive regulation of cell population proliferation	1

Protein interactions and networks

STRING

1741 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LTA	TNFRSF1A	P19438	996
LTA	LTBR	P36941	995
LTA	TNFRSF1B	P20333	994
LTA	TNFRSF14	Q92956	992
LTA	LTB	P78370	990
LTA	IL1B	P01584	857
LTA	IFNG	P01579	845
LTA	IL10	P22301	842
LTA	CXCL8	P10145	815
LTA	IL15	P40933	813
LTA	CSF2	P04141	811
LTA	IL2	P01585	780
LTA	IL1A	P01583	776
LTA	IL4	P05112	774
LTA	IL5	P05113	773
LTA	IL6	P05231	773

IntAct

31 interactions, top by confidence:

A	B	Type	Score
LTA	ANKRD40	psi-mi:“MI:0915”(physical association)	0.640
LTA	SLC30A2	psi-mi:“MI:0915”(physical association)	0.560
LTA	ASPH	psi-mi:“MI:0915”(physical association)	0.560
ABHD16A	LTA	psi-mi:“MI:0915”(physical association)	0.560
LTA	TMEM237	psi-mi:“MI:0915”(physical association)	0.560
TUBA1A	LTA	psi-mi:“MI:0915”(physical association)	0.560
LTA	LGALS2	psi-mi:“MI:0915”(physical association)	0.520
LGALS2	LTA	psi-mi:“MI:0915”(physical association)	0.520
OPG002	LTA	psi-mi:“MI:0407”(direct interaction)	0.440
LTA	LTA	psi-mi:“MI:0407”(direct interaction)	0.440
TNFRSF14	LTA	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF1B	LTA	psi-mi:“MI:0915”(physical association)	0.400
LTA	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.400
LTA	TNFRSF1A	psi-mi:“MI:0915”(physical association)	0.400
CREB3	LTA	psi-mi:“MI:0915”(physical association)	0.370
LTA	CREB3	psi-mi:“MI:0915”(physical association)	0.370
LTA	PIPSL	psi-mi:“MI:0914”(association)	0.350
LTA	BIRC2	psi-mi:“MI:0914”(association)	0.350
LTA	SLC30A2	psi-mi:“MI:0915”(physical association)	0.000
LTA	TMEM237	psi-mi:“MI:0915”(physical association)	0.000
ASPH	LTA	psi-mi:“MI:0915”(physical association)	0.000
LTA	ABHD16A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (35): CREB3 (Two-hybrid), SLC30A2 (Two-hybrid), ANKRD40 (Affinity Capture-MS), LTA (Two-hybrid), LTA (Two-hybrid), LTA (Two-hybrid), LTA (Two-hybrid), LTA (Co-crystal Structure), LTB (Reconstituted Complex), LTB (Reconstituted Complex), ANKRD40 (Affinity Capture-MS), CECR5 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), TUBA1C (Affinity Capture-MS), LTB (Affinity Capture-Western)

ESM2 similar proteins: A0EQL2, A5PJC7, D4AB34, D7PDD4, O55237, O70540, O75888, O77755, O95866, P01374, P04278, P04924, P05111, P07994, P09225, P0C6B3, P10154, P18627, P26445, P32970, P38440, P40238, P41273, P43031, P51435, P55101, P59695, P61125, Q06332, Q06600, Q08351, Q14773, Q1WM27, Q3ZDR4, Q5NKT8, Q5TM20, Q5WR07, Q61790, Q61826, Q6PGN1

Diamond homologs: O35734, O77510, O77764, P01374, P01375, P04924, P06804, P09225, P10154, P13296, P16599, P19101, P23383, P23563, P26445, P29553, P33620, P36939, P48023, P48094, P51435, P51742, P51743, P59684, P59693, P59694, P59695, P61125, P63306, P63307, P63308, P79337, P79374, Q06332, Q06599, Q06600, Q19LH4, Q1G1A2, Q1WM27, Q2MH05

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
LTA	up-regulates	LTBR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

16 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

296 predictions. Top by Δscore:

Variant	Effect	Δscore
6:31572729:TGCA:T	acceptor_loss	1.0000
6:31572730:GCAG:G	acceptor_loss	1.0000
6:31572732:AG:A	acceptor_gain	1.0000
6:31572733:G:A	acceptor_loss	1.0000
6:31572733:GG:G	acceptor_gain	1.0000
6:31572733:GGTT:G	acceptor_gain	1.0000
6:31572732:A:AG	acceptor_gain	0.9900
6:31572733:G:GT	acceptor_gain	0.9900
6:31572733:GGT:G	acceptor_gain	0.9900
6:31572733:GGTTC:G	acceptor_gain	0.9900
6:31572837:CCCAG:C	donor_loss	0.9900
6:31572838:CCAGG:C	donor_loss	0.9900
6:31572839:CAGGT:C	donor_loss	0.9900
6:31572840:AGGTG:A	donor_loss	0.9900
6:31572842:G:C	donor_loss	0.9900
6:31572843:T:A	donor_loss	0.9900
6:31572265:GGACC:G	donor_gain	0.9800
6:31572729:T:TA	acceptor_gain	0.9800
6:31573268:T:TA	acceptor_gain	0.9800
6:31573413:T:TA	donor_gain	0.9800
6:31573414:G:GA	donor_gain	0.9800
6:31573427:A:T	donor_gain	0.9800
6:31572926:AGG:A	acceptor_gain	0.9700
6:31572927:GGG:G	acceptor_gain	0.9700
6:31573269:G:A	acceptor_gain	0.9700
6:31573280:GGA:G	acceptor_gain	0.9700
6:31572299:GCAG:G	donor_gain	0.9600
6:31572300:CAGGT:C	donor_loss	0.9600
6:31572301:AG:A	donor_loss	0.9600
6:31572302:GG:G	donor_loss	0.9600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000033668 (6:31564237 C>A), RS1000136608 (6:31573328 C>T), RS1000151653 (6:31564442 G>A), RS1000495956 (6:31564637 G>C), RS1000594694 (6:31569614 G>A), RS1000802827 (6:31562886 T>G), RS1001035439 (6:31559051 A>G), RS1001295400 (6:31572559 C>T), RS1001549193 (6:31558842 C>T), RS1001815327 (6:31566079 G>A), RS1002269327 (6:31571456 C>G), RS1002740159 (6:31563647 G>T), RS1002761412 (6:31564272 T>C), RS1002967281 (6:31570845 G>A), RS1002972948 (6:31566642 G>A,T)

Disease associations

OMIM: gene MIM:153440 | disease phenotypes: MIM:608446

GenCC curated gene-disease

Mondo (1): myocardial infarction, susceptibility to (MONDO:0012039)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

38 associations (top):

Study	Trait	p-value
GCST000738_5	Neonatal lupus	5.000000e-10
GCST000879_24	Crohn’s disease	4.000000e-11
GCST002876_4	Type 1 diabetes and autoimmune thyroid diseases	2.000000e-23
GCST004131_25	Inflammatory bowel disease	2.000000e-31
GCST004133_79	Ulcerative colitis	5.000000e-65
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_126	Autism spectrum disorder or schizophrenia	2.000000e-10
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_213	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_27	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_81	Autism spectrum disorder or schizophrenia	1.000000e-14
GCST004610_15	White blood cell count	8.000000e-43
GCST004627_26	Lymphocyte count	6.000000e-72
GCST004632_121	Lymphocyte percentage of white cells	4.000000e-15
GCST005542_1	Sarcoidosis (non-Lofgren’s syndrome without extrapulmonary manifestations)	7.000000e-06
GCST008916_111	Asthma	2.000000e-14
GCST008916_114	Asthma	1.000000e-09
GCST008916_30	Asthma	1.000000e-09
GCST008917_2	Asthma (childhood onset)	4.000000e-07
GCST008921_1	Asthma and major depressive disorder	2.000000e-16
GCST010725_43	Malaria	5.000000e-07
GCST010725_62	Malaria	3.000000e-06
GCST010738_4	Tumor necrosis factor levels	3.000000e-12
GCST010979_2	Kawasaki disease	3.000000e-15
GCST012227_422	Hip circumference adjusted for BMI	1.000000e-21

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0008039	BMI-adjusted hip circumference
EFO:0005091	monocyte count
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2059 (SINGLE PROTEIN), CHEMBL3833421 (PROTEIN COMPLEX)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1800629	Efficacy	3	diclofenac	Migraine without Aura
rs1800629	Efficacy	3	ibuprofen	Migraine without Aura
rs1800629	Efficacy	3	indomethacin	Migraine without Aura
rs1800629	Efficacy	3	ketorolac	Migraine without Aura
rs1800629	Efficacy	3	naproxen	Migraine without Aura
rs1800629	Toxicity	3	carbamazepine	Hypersensitivity
rs3093726	Toxicity	3	abacavir	Drug Hypersensitivity

PharmGKB variants

11 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs909253	LTA		0.00	0
rs1041981	LTA		0.00	0
rs1799724	LTA, TNF	4	-0.88	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs1799964	LTA, TNF	3	2.50	2	Tumor necrosis factor alpha (TNF-alpha) inhibitors;stavudine
rs1800629	LST1, LTA, TNF	2B	14.62	14	etanercept;carbamazepine;ethambutol;isoniazid;pyrazinamide;rifampin;sorafenib;Tumor necrosis factor alpha (TNF-alpha) inhibitors;cyclosporine;mycophenolate mofetil;atorvastatin;carboplatin;gemcitabine;aspirin;diclofenac
rs1800630	LTA, TNF		0.00	0
rs3093726	LST1, LTA, LTB, TNF	3	0.00	1	abacavir
rs4248158	LTA, TNF		0.00	0
rs4248159	LTA, TNF		0.00	0
rs4647198	LTA, TNF		0.00	0
rs4987086	LTA, TNF		0.00	0

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.00	Kd	1e+04	nM	CHEMBL133930

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
disodium;5-isothiocyanato-2-[(E)-2-(4-isothiocyanato-2-sulfonatophenyl)ethenyl]benzenesulfonate	150323: Dissociative constant against P2Y purinoceptor (P2Y) was reported; range 10-214	kd	10.0000	uM

CTD chemical–gene interactions

65 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Curcumin	affects cotreatment, increases expression, decreases expression	3
Lipopolysaccharides	increases expression, affects response to substance, decreases expression, affects cotreatment, affects expression	3
zinc chloride	decreases expression, increases expression	2
ferrous sulfate	decreases expression, increases expression	2
usnic acid	affects cotreatment, decreases expression, increases expression	2
Resveratrol	decreases expression, affects cotreatment	2
Arsenic Trioxide	affects cotreatment, increases expression	2
Acetaminophen	affects expression, affects cotreatment, affects response to substance	2
Paraquat	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
TL8-506	affects cotreatment, increases expression	1
bisphenol A	increases expression	1
VX-agent	increases expression	1
pyrithione zinc	increases expression	1
cinnamaldehyde	increases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	affects expression	1
bromoacetate	decreases expression, increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	affects cotreatment, increases expression	1
enterotoxin A, Staphylococcal	decreases reaction, increases expression	1
1-nitropyrene	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, affects response to substance	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
monomethylarsonous acid	increases expression	1
lipopolysaccharide, E. coli O26-B6	increases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5234739	Binding	Inhibition of TNF-alpha (unknown origin) relative to control	Recent advancements in the development of heterocyclic anti-inflammatory agents. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F1PV	HyCyte HeLa KO-hLTA	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.