GDF15

Summary

GDF15 (growth differentiation factor 15, HGNC:30142) is a protein-coding gene on chromosome 19p13.11, encoding Growth/differentiation factor 15 (Q99988). Hormone produced in response to various stresses to confer information about those stresses to the brain, and trigger an aversive response, characterized by nausea, vomiting, and/or loss of appetite.

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The protein is expressed in a broad range of cell types, acts as a pleiotropic cytokine and is involved in the stress response program of cells after cellular injury. Increased protein levels are associated with disease states such as tissue hypoxia, inflammation, acute injury and oxidative stress.

Source: NCBI Gene 9518 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 61 total
• Phenotypes (HPO): 2
• Druggable target: yes
• MANE Select transcript: NM_004864

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30142
Approved symbol	GDF15
Name	growth differentiation factor 15
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	PLAB, MIC-1, PDF, MIC1, NAG-1, PTGFB
Ensembl gene	ENSG00000130513
Ensembl biotype	protein_coding
OMIM	605312
Entrez	9518

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000252809, ENST00000594925, ENST00000595973, ENST00000597765, ENST00000604609

RefSeq mRNA: 1 — MANE Select: NM_004864 NM_004864

CCDS: CCDS12376

Canonical transcript exons

ENST00000252809 — 2 exons

Exon	Start	End
ENSE00000871146	18386158	18386466
ENSE00000871147	18388286	18389176

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 98.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 151.1956 / max 6407.5784, expressed in 1558 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174650	149.6661	1539
174649	0.3103	60
174652	0.2973	152
174654	0.2452	108
174656	0.2324	87
174648	0.1942	82
174653	0.1237	66
174655	0.0937	49
174651	0.0326	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	98.08	gold quality
placenta	UBERON:0001987	97.89	gold quality
type B pancreatic cell	CL:0000169	97.10	gold quality
mucosa of urinary bladder	UBERON:0001259	97.09	gold quality
adult mammalian kidney	UBERON:0000082	94.85	gold quality
body of pancreas	UBERON:0001150	93.60	gold quality
renal medulla	UBERON:0000362	93.24	gold quality
endometrium epithelium	UBERON:0004811	91.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.49	gold quality
decidua	UBERON:0002450	91.36	gold quality
stromal cell of endometrium	CL:0002255	91.04	gold quality
kidney	UBERON:0002113	90.47	gold quality
pancreas	UBERON:0001264	90.44	gold quality
rectum	UBERON:0001052	89.96	gold quality
islet of Langerhans	UBERON:0000006	89.36	gold quality
prostate gland	UBERON:0002367	89.22	gold quality
upper lobe of left lung	UBERON:0008952	89.05	gold quality
urinary bladder	UBERON:0001255	89.01	gold quality
mucosa of transverse colon	UBERON:0004991	88.92	gold quality
nasal cavity epithelium	UBERON:0005384	88.90	gold quality
body of stomach	UBERON:0001161	88.88	gold quality
gall bladder	UBERON:0002110	88.83	gold quality
upper lobe of lung	UBERON:0008948	88.77	gold quality
cortex of kidney	UBERON:0001225	88.74	gold quality
seminal vesicle	UBERON:0000998	88.64	gold quality
nephron tubule	UBERON:0001231	87.26	gold quality
trachea	UBERON:0003126	86.36	gold quality
nasal cavity mucosa	UBERON:0001826	85.82	gold quality
kidney epithelium	UBERON:0004819	85.60	gold quality
stomach	UBERON:0000945	85.03	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-24	yes	2355.41
E-HCAD-15	yes	2314.30
E-CURD-114	yes	970.06
E-MTAB-8530	yes	880.68
E-MTAB-10018	yes	843.72
E-MTAB-6701	yes	47.56
E-HCAD-10	yes	20.39
E-GEOD-125970	yes	19.28
E-MTAB-5061	yes	19.15
E-MTAB-6678	yes	6.49
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF3, CEBPB, EGR1, HR, KLF4, NFKB, PARP1, PITX1, PPARG, RELA, SP1, SP3, SSRP1, TP53, TP63, TWIST1, TWIST2

miRNA regulators (miRDB)

7 targeting GDF15, 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-6740-5P	100.00	65.64	932
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-499B-5P	98.35	68.39	988

Literature-anchored findings (GeneRIF, showing 40)

• Unlike other TGF-b cytokines, MIC-1 is able to be expressed correctly folded without its propeptide. A 28 aa propeptide epitope contains a quality control signal which can signal misfolding of MIC-1, leading to proteasomal degradation. (PMID:10811612)
• MIC-1 is present in large amounts in placenta and amniotic fluid. Very high levels of MIC-1 are present in the sera of pregnant women and rise substantially with progress of gestation (PMID:11134143)
• At least five immunogenic regions on the MIC-1 surface can be detected by MAbs. One MAb is directed against the amino terminus of the protein and can distinguish between the two allelic forms of MIC-1 (PMID:11141057)
• NAG-1 is an antitumorigenic and proapoptotic protein, and its regulation by COX inhibitors may provide new clues for explaining their proapoptotic and antitumorigenic activities. (PMID:11259636)
• Propeptide deletion mutants of MIC-1 enabled identification of a region between residues 56 and 78, which is important for the interaction between the propeptide and the mature peptide during folding (PMID:11278594)
• the level of expression of the NAG-1 gene will depend on the availability of Sp proteins and on co-factors such as chicken ovalbumin upstream promoter-transcription factor 1 (PMID:11445565)
• Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53 (PMID:11895857)
• report that autocrine hGH production by mammary carcinoma cells specifically results in the transcriptional repression of the p53-regulated placental transforming growth factor-beta gene (Placental growth factor-beta; TGF-beta) (PMID:11994274)
• placental transforming growth factor-beta as an important downstream mediator of DNA damage signaling and a transcriptional target of p53 (PTGF-beta) (PMID:12011055)
• Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1. MIC-1 is an important downstream mediator of p53 function and intercessor of cellular stress signaling and exerting antitumorigenic activities. (PMID:12082608)
• In the experimental model MIC-1 may exert anti-tumorigenic properties via a paracrine mechanism mediated by host cells in vivo. MIC-1 is an important downstream mediator of p53 function (PMID:12082608)
• MIC-1 serum levels were higher at baseline in women who later had cardiovascular events. Levels > 90th percentile were associated with a 2.7x greater risk and independent of traditional cardiovascular risk factors and at least additive to that of CRP (PMID:12090982)
• There are at least two alleles of MIC-1 that are due to a G–>C point substitution at position 6 of the mature protein, which alters a his to an asp (MIC-1 H and MIC-1 D). The frequency of the 3 common MIC-1 genotypes was: HH 54%; HD 39%; DD 7% (PMID:12139236)
• GDF-15 prevents apoptosis in cerebellar granule neurons by activating Akt and inhibiting endogenously active ERK (PMID:12514175)
• Microarray analysis identifies MIC-1 as being upregulated in cancer of breast, prostate, and colon. Tissues from these patients show increased MIC-1 by IHC and their serum shows elevated levels (PMID:12624183)
• There is a strong association between MIC-1 serum levels and neoplastic progression (polyps to cancer) within the large bowel and significant differences in time to relapse and overall survival between subjects with different MIC-1 levels and genotypes (PMID:12855642)
• Decreased NAG-1 expression in higher grade cancer is consistent with its known antitumorigenic, proapoptotic activities. (PMID:12894347)
• amniotic fluid MIC-1 is derived from the fetal membranes and decidua, but that MIC-1 is unlikely to be involved in the pathophysiology of preterm birth or premature rupture of membranes (PMID:12900512)
• Treating DU145 prostate cancer cells with MIC-1 causes loss of adhesion and consequently induces cell detachment and apoptosis. This is mediated at least in part by reduction in metallothionein 1E, RhoE and catenin delta 1. (PMID:12941831)
• NAG-1 may be involved in differentiation and apoptotic processes of nasal epithelial cells. It is still unclear whether NAG-1 is an inducer or a byproduct of differentiation or apoptosis (PMID:14575402)
• expression of NAG-1 by troglitazone requires the early growth response gene EGR-1 (PMID:14662774)
• Serum MIC-1 levels are markedly depressed in women, some weeks before miscarriage and at a time when the fetus is still viable. This suggests possible predictive and causative roles, as well as therapeutic potential (PMID:14726168)
• MIC-1 has a role in progression of primary pancreatic cancers, intraductal papillary mucinous neoplasms, and pancreatic cancer (PMID:15073115)
• The combination of serum levels of MIC-1 and CA19-9 significantly improved diagnostic accuracy of pancreatic cancer (sensitivity, 70%; specificity, 85%) (PMID:15073115)
• This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility (PMID:15316060)
• Findings suggest that early prostate carcinogenesis is associated with expression of mature GDF15 protein. (PMID:15342369)
• The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells. (PMID:15670751)
• expression levels may serve as a surrogate marker for the AKT activation in tumors (PMID:15677629)
• NAG-1 expression is up-regulated by TPA in LNCaP cells through a PKC-dependent pathway involving the activation of NF-kappa B (PMID:15757899)
• GDF-15 induction is an immediate early response to liver injury that can occur through TNF and p53 independent pathways (PMID:16154591)
• t10,c12-CLA stimulates ATF3/NAG-1 expression and subsequently induces apoptosis in an isomer specific manner (PMID:16286461)
• An additional serum marker for the detection of prostatic cancer. (PMID:16388506)
• GDF-15 expression increased within 12 hours of symptom onset and remained upregulated for at least 2 weeks after myocardial infarct. (PMID:16397141)
• highly expressed in the placenta and the prostate, but not normally in many other organs, including the heart (PMID:16484622)
• Study suggests that proapoptotic activity of NAG-1 is cell type specific and not related to COX-2 expression. (PMID:16699947)
• Induction of message and protein in prostate cancer cells requires 1alpha, 25-dihydroxyvitamin D3. (PMID:16741990)
• Single Nucleotide Polymorphisms in Macrophage inhibitory cytokine-1 is associated with prostate cancer (PMID:16775185)
• Stimulation of macrophage inhibitory cytokine 1-dependent S phase arrest in normal gut epithelial cells might help to revitalize the clinical use of N-phosphonacetyl-l-aspartate, which has been limited by gut toxicity (PMID:17050687)
• Serum levels of MIC-1 and MIC-1 genotype may be clinically useful in the management of rheumatoid arthritis as well as in selection of patients for hemopoietic stem cell transplantation, since they predict disease course and response to therapy. (PMID:17328047)
• study does not support the role of common genetic variation at MIC1 and IL1RN in prostate cancer susceptibility (PMID:17548705)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Gdf15	ENSMUSG00000038508
rattus_norvegicus	Gdf15	ENSRNOG00000019661

Paralogs (31): TGFB2 (ENSG00000092969), BMP7 (ENSG00000101144), TGFB1 (ENSG00000105329), BMP5 (ENSG00000112175), BMP8B (ENSG00000116985), TGFB3 (ENSG00000119699), INHBA (ENSG00000122641), INHA (ENSG00000123999), BMP4 (ENSG00000125378), BMP2 (ENSG00000125845), GDF5 (ENSG00000125965), GDF1 (ENSG00000130283), BMP15 (ENSG00000130385), GDF11 (ENSG00000135414), MSTN (ENSG00000138379), INHBE (ENSG00000139269), LEFTY2 (ENSG00000143768), GDF7 (ENSG00000143869), BMP3 (ENSG00000152785), BMP6 (ENSG00000153162), GDF6 (ENSG00000156466), NODAL (ENSG00000156574), INHBB (ENSG00000163083), BMP10 (ENSG00000163217), GDF9 (ENSG00000164404), INHBC (ENSG00000175189), BMP8A (ENSG00000183682), GDF3 (ENSG00000184344), LEFTY1 (ENSG00000243709), GDF2 (ENSG00000263761), GDF10 (ENSG00000266524)

Protein

Protein identifiers

Growth/differentiation factor 15 — Q99988 (reviewed: Q99988)

Alternative names: Macrophage inhibitory cytokine 1, NSAID-activated gene 1 protein, NSAID-regulated gene 1 protein, Placental TGF-beta, Placental bone morphogenetic protein, Prostate differentiation factor

All UniProt accessions (2): Q99988, A0A0A0MTT8

UniProt curated annotations — full annotation on UniProt →

Function. Hormone produced in response to various stresses to confer information about those stresses to the brain, and trigger an aversive response, characterized by nausea, vomiting, and/or loss of appetite. The aversive response is both required to reduce continuing exposure to those stresses at the time of exposure and to promote avoidance behavior in the future. Acts by binding to its receptor, GFRAL, activating GFRAL-expressing neurons localized in the area postrema and nucleus tractus solitarius of the brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitutes part of the ’emergency circuit’ that shapes responses to stressful conditions. The GDF15-GFRAL signal induces expression of genes involved in metabolism, such as lipid metabolism in adipose tissues. Required for avoidance behavior in response to food allergens: induced downstream of mast cell activation to promote aversion and minimize harmful effects of exposure to noxious substances. In addition to suppress appetite, also promotes weight loss by enhancing energy expenditure in muscle: acts by increasing calcium futile cycling in muscle. Contributes to the effect of metformin, an anti-diabetic drug, on appetite reduction and weight loss: produced in the kidney in response to metformin treatment, thereby activating the GDF15-GFRAL response, leading to reduced appetite and weight. The contribution of GDF15 to weight loss following metformin treatment is however limited and subject to discussion. Produced in response to anticancer drugs, such as camptothecin or cisplatin, promoting nausea, vomiting and contributing to malnutrition. Overproduced in many cancers, promoting anorexia in cancer (cachexia). Responsible for the risk of nausea and vomiting during pregnancy: high levels of GDF15 during pregnancy, mostly originating from the fetus, are associated with increased nausea and vomiting. Maternal sensitivity to nausea is probably determined by pre-pregnancy exposure to GDF15, women with naturally high level of GDF15 being less susceptible to nausea than women with low levels of GDF15 before pregnancy. Promotes metabolic adaptation in response to systemic inflammation caused by bacterial and viral infections in order to promote tissue tolerance and prevent tissue damage. Required for tissue tolerance in response to myocardial infarction by acting as an inhibitor of leukocyte integring activation, thereby protecting against cardiac rupture. Inhibits growth hormone signaling on hepatocytes.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with GFRAL and RET; ligand of GFRAL, which mediates GDF15 internalization and cellular signaling through interaction with RET via the formation of a 2:2:2 ternary complex composed of GDF15, GFRAL and RET.

Subcellular location. Secreted.

Tissue specificity. Detected in plasma (at protein level). Highly expressed in placenta, with lower levels in prostate and colon and some expression in kidney.

Disease relevance. Hyperemesis gravidarum (HG) [MIM:620730] An autosomal dominant condition characterized by severe nausea and vomiting in pregnancy. It occurs in up to 2% of pregnancies and leads to significant weight loss, dehydration, electrolyte imbalance, and ketonuria. It is associated with both maternal and fetal morbidity. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Induction. Produced in response to various stresses, such as metabolic and toxin-induced stresses or drugs. Expression is activated by ATF4 and DDIT3/CHOP transcription factors downstream of the integrated stress response (ISR). Expressed in response to inflammatory conditions. Expression is induced by metformin, a blood-glucose-lowering drug. Expression is induced by cisplatin anticancer drug. Also induced by physical activity. Expression is up-regulated by obesity. Expression is up-regulated by ketogenic diet.

Miscellaneous. GDF15 was initially considered as a promising factor for the treatment of obesity due to its ability of GDF15 to reduce appetite and promote weight loss. However, while activation of the GDF15-GFRAL signaling pathway is efficient to reduce obesity and promote weight loss in mouse, it only has limited effect in human.

Similarity. Belongs to the TGF-beta family.

RefSeq proteins (1): NP_004855* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001839	TGF-b_C	Domain
IPR015615	TGF-beta-like	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF00019

UniProt features (33 total): mutagenesis site 6, strand 6, disulfide bond 5, sequence variant 4, turn 3, sequence conflict 2, signal peptide 1, propeptide 1, chain 1, helix 1, region of interest 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5VZ3	X-RAY DIFFRACTION	1.97
5VZ4	X-RAY DIFFRACTION	2.2
5VT2	X-RAY DIFFRACTION	2.3
6Q2J	ELECTRON MICROSCOPY	4.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99988-F1	76.17	0.32

Functional residue map

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

Disulfide bonds (5): 273, 203–210, 211–274, 240–305, 244–307

Glycosylation sites (1): 70

Mutagenesis-validated functional residues (6):

Position	Phenotype
225	no effect on interaction with gfral. attenuates gdf15-mediated food-intake inhibition.
228	abolished formation of a ternary complex with gfral and ret.
283	reduces cellular signaling mediated by gfral and ret.
283	abolishes interaction with gfral. abolishes ret phosphorylation and cellular signaling mediated by gfral and ret.
285	reduces cellular signaling mediated by gfral and ret. abolishes interaction with gfral and gdf15-mediated food-intake in
297	abolished formation of a ternary complex with gfral and ret.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 480 (showing top): GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_LIPID_MODIFICATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_52, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, LEE_NEURAL_CREST_STEM_CELL_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_BEHAVIOR, chr16q22, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_RESPONSE_TO_DIETARY_EXCESS, GOZGIT_ESR1_TARGETS_DN, CHUANG_OXIDATIVE_STRESS_RESPONSE_UP

GO Biological Process (19): reduction of food intake in response to dietary excess (GO:0002023), negative regulation of leukocyte migration (GO:0002686), signal transduction (GO:0007165), cell surface receptor protein serine/threonine kinase signaling pathway (GO:0007178), transforming growth factor beta receptor signaling pathway (GO:0007179), cell-cell signaling (GO:0007267), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), negative regulation of appetite (GO:0032099), negative regulation of multicellular organism growth (GO:0040015), positive regulation of MAPK cascade (GO:0043410), positive regulation of fatty acid oxidation (GO:0046321), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), negative regulation of SMAD protein signal transduction (GO:0060392), negative regulation of growth hormone receptor signaling pathway (GO:0060400), cellular response to chemical stress (GO:0062197), GDF15-GFRAL signaling pathway (GO:0160144), response to metformin (GO:1901558), positive regulation of myoblast fusion (GO:1901741), energy homeostasis (GO:0097009)

GO Molecular Function (5): cytokine activity (GO:0005125), hormone activity (GO:0005179), growth factor activity (GO:0008083), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), extracellular exosome (GO:0070062), extracellular matrix (GO:0031012)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
receptor ligand activity	3
cell communication	2
signaling	2
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
positive regulation of intracellular signal transduction	2
cellular response to stress	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
response to dietary excess	1
eating behavior	1
negative regulation of immune system process	1
regulation of leukocyte migration	1
negative regulation of cell migration	1
leukocyte migration	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
cellular response to transforming growth factor beta stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
transforming growth factor beta receptor signaling pathway	1
regulation of transforming growth factor beta receptor signaling pathway	1
negative regulation of response to food	1
regulation of appetite	1
multicellular organism growth	1
regulation of multicellular organism growth	1
negative regulation of developmental growth	1
negative regulation of multicellular organismal process	1
MAPK cascade	1
regulation of MAPK cascade	1
fatty acid oxidation	1
positive regulation of fatty acid metabolic process	1
regulation of fatty acid oxidation	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of SMAD protein signal transduction	1
SMAD protein signal transduction	1
negative regulation of intracellular signal transduction	1
negative regulation of signal transduction	1
growth hormone receptor signaling pathway	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

74 interactions, top by confidence:

A	B	Type	Score
KBTBD7	METTL15	psi-mi:“MI:0914”(association)	0.730
MDFI	GDF15	psi-mi:“MI:0915”(physical association)	0.700
KRTAP12-2	GDF15	psi-mi:“MI:0915”(physical association)	0.560
GDF15	TACC3	psi-mi:“MI:0915”(physical association)	0.560
HOXA1	GDF15	psi-mi:“MI:0915”(physical association)	0.560
CBX3	GDF15	psi-mi:“MI:0915”(physical association)	0.560
GDF15	GFRAL	psi-mi:“MI:0407”(direct interaction)	0.560
	PLOD2	psi-mi:“MI:0914”(association)	0.530
C1orf54	EXTL3	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
GDF15	GDF15	psi-mi:“MI:0407”(direct interaction)	0.440
GDF15	NLGN3	psi-mi:“MI:0915”(physical association)	0.370
Cdc37	STX18	psi-mi:“MI:0914”(association)	0.350
STAT5A	R3HDM2	psi-mi:“MI:0914”(association)	0.350
Smn1	CLNS1A	psi-mi:“MI:0914”(association)	0.350
NUP58	ABCC5	psi-mi:“MI:0914”(association)	0.350
SAE1	PQBP1	psi-mi:“MI:0914”(association)	0.350
SETD4	TADA3	psi-mi:“MI:0914”(association)	0.350
Trip11	PPL	psi-mi:“MI:0914”(association)	0.350
MRPL50	MRPL43	psi-mi:“MI:0914”(association)	0.350
RMND5A	HTRA2	psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
PRKCB	CHEK1	psi-mi:“MI:0914”(association)	0.350
PRKD1		psi-mi:“MI:0914”(association)	0.350
TAGLN	LOC392647	psi-mi:“MI:0914”(association)	0.350

BioGRID (79): GDF15 (Affinity Capture-MS), GDF15 (Affinity Capture-MS), GDF15 (Affinity Capture-MS), GDF15 (Affinity Capture-MS), GDF15 (Affinity Capture-MS), GDF15 (Affinity Capture-MS), GDF15 (Affinity Capture-MS), GDF15 (Affinity Capture-MS), GDF15 (Two-hybrid), GDF15 (Affinity Capture-MS), GDF15 (Affinity Capture-MS), GDF15 (Two-hybrid), GDF15 (Two-hybrid), GDF15 (Two-hybrid), GDF15 (Two-hybrid)

ESM2 similar proteins: A0A1B0GTW7, A0A1D5NSK0, A0A1L8HYT7, A0A286YEC0, D3ZT86, D3ZWJ9, D4A929, F8W3R9, G7PWZ3, I6M4H4, O08852, O43157, O43278, O75074, O88204, P17813, P49000, P59383, Q04912, Q17R55, Q499Z3, Q4R3B7, Q4TUC0, Q5ND34, Q62190, Q63961, Q6AXX1, Q76MJ5, Q7TN88, Q7TQH7, Q7Z442, Q7Z4F1, Q80W87, Q80YN4, Q866Y3, Q86VZ4, Q8BHW9, Q8BMN4, Q8BYI8, Q8BZT7

Diamond homologs: G5EEL5, G7PWZ3, O77681, P18075, P20722, P22003, P22004, P23359, P30886, P34820, P43028, P43029, P49003, P55107, P55108, Q04906, Q26974, Q66NC0, Q6HA10, Q6KF10, Q7Z4P5, Q7Z5Y6, Q99988, Q9BDW8, Q9GK68, Q9Z0J6, Q9Z0J7, A8E7N9, A9CB18, O08717, O13048, O19006, O46564, O46576, O60383, O61643, O88959, O95393, O95972, P03970

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ATF3	“up-regulates quantity by expression”	GDF15	“transcriptional regulation”
CEBPB	“up-regulates quantity by expression”	GDF15	“transcriptional regulation”
EGR1	“up-regulates quantity by expression”	GDF15	“transcriptional regulation”
TWIST2	“up-regulates quantity by expression”	GDF15	“transcriptional regulation”
TWIST1	“up-regulates quantity by expression”	GDF15	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	50
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

62 predictions. Top by Δscore:

Variant	Effect	Δscore
19:18386462:AGAAG:A	donor_gain	1.0000
19:18386463:GAAG:G	donor_gain	1.0000
19:18386463:GAAGG:G	donor_gain	1.0000
19:18386464:AAG:A	donor_gain	1.0000
19:18386465:AG:A	donor_gain	1.0000
19:18386466:GG:G	donor_gain	1.0000
19:18386466:GGTA:G	donor_loss	1.0000
19:18386467:G:GG	donor_gain	1.0000
19:18386467:GTAA:G	donor_loss	1.0000
19:18388284:A:AG	acceptor_gain	1.0000
19:18388285:G:GA	acceptor_gain	1.0000
19:18388280:CCACA:C	acceptor_loss	0.9900
19:18388281:CACAG:C	acceptor_loss	0.9900
19:18388283:C:G	acceptor_gain	0.9900
19:18388283:CAGTG:C	acceptor_loss	0.9900
19:18388284:A:AC	acceptor_loss	0.9900
19:18388284:AGT:A	acceptor_gain	0.9900
19:18388284:AGTGC:A	acceptor_gain	0.9900
19:18388285:GT:G	acceptor_gain	0.9900
19:18388285:GTG:G	acceptor_gain	0.9900
19:18388285:GTGC:G	acceptor_gain	0.9900
19:18388285:GTGCG:G	acceptor_gain	0.9900
19:18386467:G:T	donor_gain	0.9800
19:18388282:ACAGT:A	acceptor_gain	0.9800
19:18388282:A:AG	acceptor_gain	0.9700
19:18387802:G:T	donor_gain	0.9000
19:18388273:T:TA	acceptor_gain	0.8900
19:18388289:G:A	acceptor_gain	0.7000
19:18388192:G:GT	donor_gain	0.6800
19:18388286:T:TA	acceptor_gain	0.6600

AlphaMissense

1936 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:18388732:G:T	G242C	0.998
19:18388683:G:C	W225C	0.997
19:18388683:G:T	W225C	0.997
19:18388692:G:C	W228C	0.996
19:18388692:G:T	W228C	0.996
19:18388726:T:A	C240S	0.996
19:18388727:G:C	C240S	0.996
19:18388733:G:T	G242V	0.996
19:18388728:C:G	C240W	0.994
19:18388738:T:A	C244S	0.994
19:18388739:G:C	C244S	0.994
19:18388828:T:A	C274S	0.994
19:18388829:G:C	C274S	0.994
19:18388727:G:A	C240Y	0.993
19:18388829:G:A	C274Y	0.993
19:18388835:C:A	P276H	0.992
19:18388927:T:A	C307S	0.992
19:18388928:G:C	C307S	0.992
19:18388726:T:C	C240R	0.991
19:18388738:T:C	C244R	0.991
19:18388739:G:A	C244Y	0.990
19:18388830:C:G	C274W	0.990
19:18388928:G:A	C307Y	0.990
19:18388929:C:G	C307W	0.990
19:18388640:G:A	C211Y	0.989
19:18388750:T:C	F248L	0.989
19:18388752:C:A	F248L	0.989
19:18388752:C:G	F248L	0.989
19:18388828:T:C	C274R	0.989
19:18388922:G:A	C305Y	0.989

dbSNP variants (sampled 300 via entrez): RS1000290705 (19:18386761 C>G,T), RS1000641221 (19:18387158 A>C,G), RS1002465534 (19:18384767 T>C), RS1003080580 (19:18385151 T>C), RS1004319159 (19:18384576 C>G,T), RS1005183469 (19:18384197 C>G,T), RS1005268184 (19:18389045 C>T), RS1005475240 (19:18389375 T>A), RS1005815059 (19:18387712 C>T), RS1006702471 (19:18385017 C>A,T), RS1007244602 (19:18389091 CCTT>C), RS1007652786 (19:18387581 C>T), RS1007702081 (19:18387312 T>G), RS1008652060 (19:18386096 C>A), RS1008706154 (19:18385806 A>G)

Disease associations

OMIM: gene MIM:605312 | disease phenotypes: MIM:620730

GenCC curated gene-disease

Mondo (1): hyperemesis gravidarum, susceptibility to (MONDO:0958238)

Orphanet (0):

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0012188	Hyperemesis gravidarum

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST005711_1	Growth differentiation factor-15 levels	3.000000e-35
GCST005929_1	Severity of nausea and vomiting of pregnancy	2.000000e-41
GCST005930_1	Hyperemesis gravidarum	2.000000e-19
GCST006585_1595	Blood protein levels	3.000000e-69
GCST008526_56	Coffee consumption	1.000000e-08
GCST009731_75	Blood protein levels in cardiovascular risk	6.000000e-15
GCST90013406_164	Liver enzyme levels (alkaline phosphatase)	4.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009265	nausea and vomiting of pregnancy severity measurement
EFO:0006781	coffee consumption measurement
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3120039 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression, affects acetylation, affects methylation, affects cotreatment	10
Benzo(a)pyrene	increases expression	10
Doxorubicin	decreases expression, increases expression, decreases response to substance	9
Cisplatin	affects expression, decreases expression, decreases reaction, increases expression, affects reaction	8
Estradiol	decreases expression, increases expression, affects cotreatment	8
Indomethacin	decreases response to substance, increases expression, affects cotreatment, decreases expression	8
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases reaction, affects expression, decreases expression	8
Aflatoxin B1	affects expression, affects cotreatment, increases expression	8
bisphenol A	affects expression, increases expression, increases secretion	7
sulindac sulfide	increases expression, increases reaction	7
Hydrogen Peroxide	affects expression, affects cotreatment, decreases expression, increases expression	7
Cyclosporine	increases expression	7
Cadmium Chloride	decreases expression, increases abundance, increases expression, affects cotreatment	6
Troglitazone	affects binding, affects reaction, decreases reaction, increases expression	5
Valproic Acid	affects expression, increases expression	5
Particulate Matter	increases abundance, increases expression, affects cotreatment, decreases expression	5
Celecoxib	affects cotreatment, increases expression, decreases reaction, affects reaction	4
Arsenic Trioxide	increases expression	4
Etoposide	affects binding, increases expression, increases reaction	4
Fluorouracil	affects reaction, increases expression	4
Oxygen	decreases expression, decreases reaction, increases expression	4
SB 203580	affects cotreatment, decreases reaction, increases expression	3
Rosiglitazone	increases expression	3
Resveratrol	increases reaction, decreases reaction, increases expression, affects cotreatment, affects binding	3
Decitabine	affects expression, affects methylation, increases reaction	3
Ibuprofen	decreases reaction, increases expression, increases reaction	3
Paraquat	increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Tretinoin	increases expression, decreases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	3

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3124366	Binding	Activation of NAG-1 in human SW1353 cells at 20 uM after 24 hrs by luciferase reporter gene assay relative to vehicle-treated control	Octulosonic acid derivatives from Roman chamomile (Chamaemelum nobile) with activities against inflammation and metabolic disorder. — J Nat Prod

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1QS	HyCyte HT-29 KO-hGDF15	Cancer cell line	Female

Clinical trials (associated diseases)

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