UGT1A

Summary

UGT1A (UDP glucuronosyltransferase family 1 member A complex locus, HGNC:12529) is a protein-coding gene on chromosome 2q37. In precision oncology, UGT1A EXPRESSION is associated with resistance to Ganetespib in Colorectal Cancer (CIViC Level D).

This RefSeq represents a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5’ exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter.

Source: NCBI Gene 7361 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 536 total — 12 pathogenic, 5 likely-pathogenic
• Precision-oncology evidence (CIViC): 1 curated variant–drug association

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12529
Approved symbol	UGT1A
Name	UDP glucuronosyltransferase family 1 member A complex locus
Location	2q37
Locus type	gene with protein product
Status	Approved
Aliases	UGT
Entrez	7361

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

None — 0 exons

Expression profiles

Top tissues by expression

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

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 39)

• we suggest that UGTs constitutive expression in the normal mucosa could protect these organs from carcinogens released in the bladder or introduced directly with the diet in the colon. (PMID:15643497)
• Because of possible substrate overlap regarding UGT1A isoforms, determination of haplotypes should be considered in pharmacogenetic studies with drugs that undergo glucuronidation. (PMID:16909274)
• first direct evidence of a novel alternative splicing mechanism at the 3’ end of the UGT1 locus that further increases the number of proteins derived from this single gene (PMID:18004212)
• Chinese patients exhibit less irinotecan-related diarrhea due to higher frequence of UGT1A A1 * 28 wild genotype TA6/6. (PMID:18478930)
• comprehensively determined the expression of all functional UGT1A and UGT2B isoforms in normal human tissues including liver, lung, stomach, small intestine, colon, kidney, bladder, adrenal gland, breast, ovary, uterus, and testis by RT-PCR (PMID:18480185)
• The data strongly implicates the UGT1A locus, rather than merely a single isolated SNP, as an important mediator of irinotecan-associated activity (PMID:19364959)
• coordinated AhR- and Nrf2-dependent transcriptional regulation of human UGT1A8 and UGT1A10 (PMID:20053997)
• UGT1A1 was the most efficient conjugating enzyme with K(m) values of </=1 muM and relative catalytic efficiency ratios of >/=5.5. (PMID:21472492)
• The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan (PMID:21691256)
• Weak or moderate positivity of UGT1A was significantly associated with bladder tumor progression. (PMID:22086872)
• The common UGT1A1*28 polymorphism influences bisphenol A (BPA) glucuronidation, and consequently, BPA detoxification. (PMID:22154984)
• a haplotype of multiple genetic variants at the UGT1A gene locus, which is present in a vast majority of Gilbert syndrome (GS) individuals. (PMID:22213127)
• This review discusses the recent progress in modeling human UGT substrates. (PMID:22385482)
• The molecular analysis of the UGT1A1 gene promoter showed that father and mother had the heterozygous mutation, an insertion of a dinucleotide ‘TA repeat’[A(TA)6TAA/A(TA)7TAA]. (PMID:22407023)
• Available data suggest association between an SNP in intronic region of UGT1A locus (rs11892031[A]) on chromosome 2q37.1 and urinary bladder cancer risk following exposure to bladder-specific carcinogens. [META-ANALYSIS] (PMID:22532026)
• UGT1A*60 showed no association with neutropenia (PMID:22535333)
• UGT1A region is the major regulator of bilirubin metabolism and associated with cholelithiasis in African Americans with sickle cell anemia. (PMID:22558097)
• The decreased expression of UGT1A and the dysregulation of Nrf2/Keap1 system may play a role in colonic tumorigenesis. (PMID:22943825)
• We identified two new skin color genes: genetic variants in UGT1A were significantly associated with hue and variants in BNC2 were significantly associated with saturation. (PMID:23052946)
• UGT1A is likely regulated by estrogens in non-neoplastic urothelium versus bladder tumor in opposite manners, which could be underlying mechanisms of gender-specific differences in bladder cancer incidence and progression (PMID:23143693)
• relative protein abundance of UGT1A alternative splice variants is a key determinant of glucuronidation activity in vitro (PMID:23360619)
• results indicate that a common single nucleotide polymorphism (SNP) in the UDP-glucuronosyltransferase 1A (UGT1A) gene (rs8330) is associated with increased hepatic acetaminophen glucuronidation, possibly through effects on UGT1A gene splicing (PMID:23408116)
• Regulation of human UGT1A genes is tissue-specific. Individual variation in polymorphic expressions of UGTlA gene locus was noted in all types of colonic tissue tested, whereas hepatic tissue expression was uniform. (PMID:23468910)
• These findings support a potential role for UGT1A genetic variants in risk for mortality in type 2 diabetes. (PMID:23642732)
• A deficiency of UGT1A was identified in prostate stem cells. UGT1A was also downregulated in cancer stem cells, and during progression to metastatic castration-resistant prostate cancer. (PMID:23880823)
• UGT genetic variation alters CRC risk differently by anatomical sub-site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk. (PMID:24822274)
• The number of UGT1A1 reduced function alleles was associated with decreased SN-38G formation rates. (PMID:24897286)
• study demonstrates that the Japanese HIV-1-infected patients who developed atazanavir-induced nephrolithiasis were approximately 5-fold more likely to have variants in the UGT1A-3’-untranslated region compared with those without nephrolithiasis (PMID:25151207)
• The study identified several UGT1A genotypes and several haplotypes associated with the irinotecan toxicity. (PMID:25175642)
• Article discusses the variabilities in the genes encoding the drug target (CYP19A1) or its metabolizing enzymes (CYP3A and UGT1A) and its influence toward the interindividual variability in anastrozole’s pharmacokinetics and/or pharmacodynamics.[Review] (PMID:25203739)
• UDP glucuronosyltransferase 1A expression levels determine the response of colorectal cancer cells to ganetespib. (PMID:25210794)
• in tumor liver microsomes from HCC patients, either V(max) (maximum reaction rate, R(max) for UGT1A1) or clearance rates (V(max)/K(m), Clint) of UGT1A, UGT1A1, UGT1A4, UGT1A9 and UGT2B7 were lower than those in the adjacent normal liver microsomes (PMID:26010150)
• Alternate UGT1A variants may thus be part of the expanding compendium of metabolic pathways involved in cancer biology. (PMID:28049773)
• UGT1A7*3 allele emerged as a protective marker for hepatocellular carcinoma (HCC) development among both high-risk HBV/HCV-positive patients and healthy subjects. (PMID:28294511)
• a common UGT1A haplotype, prevalent in 9% (homozygous) of the White population, significantly impairs the expression of UGT1A enzymes capable of cellular detoxification, which profoundly affects the physiological responsiveness towards the putative tobacco and environmental carcinogen benzo[alpha]pyrene (PMID:28300668)
• The study demonstrates that miR-298 and miR-491-3p downregulates UGT1A expression. (PMID:29172698)
• Genotypes of UGT1A and ABCB1 were significantly associated with changes in moxifloxacin pharmacokinetic parameters. (PMID:29210323)
• Regulation of uridine diphosphate-glucuronosyltransferase 1A expression by miRNA-214-5p and miRNA-486-3p. (PMID:33432840)
• The Activity of Members of the UDP-Glucuronosyltransferase Subfamilies UGT1A and UGT2B is Impaired in Patients with Liver Cirrhosis. (PMID:37328712)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Canonical reviewed UniProt: None (reviewed: )

All UniProt accessions (0):

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (0):

GO Molecular Function (0):

GO Cellular Component (0):

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

0 interactions, top by confidence:

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	5
Uncertain significance	393
Likely benign	89
Benign	17

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1070066	NM_000463.3(UGT1A1):c.679dup (p.Tyr227fs)	Pathogenic
12273	NM_000463.3(UGT1A1):c.840C>A (p.Cys280Ter)	Pathogenic
12282	NC_000002.12:g.233758936=	Pathogenic
1338379	NM_000463.3(UGT1A1):c.1043del (p.Asn348fs)	Pathogenic
1338452	NM_000463.3(UGT1A1):c.269_270del (p.Glu90fs)	Pathogenic
1458334	NM_000463.3(UGT1A1):c.72dup (p.Ser25fs)	Pathogenic
1459340	NM_000463.3(UGT1A1):c.977T>A (p.Leu326Ter)	Pathogenic
2634101	NM_000463.2(UGT1A1):c.-85_-83dupCAT	Pathogenic
285285	NM_000463.3(UGT1A1):c.1069C>T (p.Gln357Ter)	Pathogenic
3346165	NM_000463.3(UGT1A1):c.755_756del (p.Ser252fs)	Pathogenic
3720423	NM_000463.3(UGT1A1):c.488_491dup (p.Ser165fs)	Pathogenic
437210	NM_000463.3(UGT1A1):c.222C>A (p.Tyr74Ter)	Pathogenic
1330395	NM_000463.3(UGT1A1):c.996+1G>A	Likely pathogenic
1338357	NM_000463.3(UGT1A1):c.996+2_996+5del	Likely pathogenic
2231117	NM_000463.3(UGT1A1):c.1007G>T (p.Arg336Leu)	Likely pathogenic
3347178	NM_000463.3(UGT1A1):c.1435del (p.His479fs)	Likely pathogenic
4086056	NM_000463.3(UGT1A1):c.1385T>A (p.Val462Glu)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

Disease associations

OMIM: gene `` | disease phenotypes: MIM:218800, MIM:143500, MIM:237900, MIM:606785

GenCC curated gene-disease

Mondo (6): Crigler-Najjar syndrome type 1 (MONDO:0021020), Gilbert syndrome (MONDO:0007745), transient familial neonatal hyperbilirubinemia (MONDO:0009383), Crigler-Najjar syndrome type 2 (MONDO:0011725), hyperbilirubinemia (MONDO:0024288), Crigler-Najjar syndrome (MONDO:0009044)

Orphanet (5): Crigler-Najjar syndrome type 1 (Orphanet:79234), Crigler-Najjar syndrome (Orphanet:205), Transient familial neonatal hyperbilirubinemia (Orphanet:2312), Crigler-Najjar syndrome type 2 (Orphanet:79235), NON RARE IN EUROPE: Gilbert syndrome (Orphanet:357)

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST000842_3	Bladder cancer	1.000000e-07
GCST001091_2	Bilirubin levels	5.000000e-62
GCST001217_14	Metabolic traits	3.000000e-74
GCST001976_1	Bilirubin levels	9.000000e-20
GCST002240_1	Bladder cancer	1.000000e-07
GCST002388_16	Serum metabolite levels	1.000000e-17
GCST002388_17	Serum metabolite levels	6.000000e-13
GCST002388_18	Serum metabolite levels	8.000000e-23
GCST002745_10	Total bilirubin levels in HIV-1 infection	1.000000e-30
GCST002745_11	Total bilirubin levels in HIV-1 infection	3.000000e-24
GCST002745_2	Total bilirubin levels in HIV-1 infection	5.000000e-16
GCST002745_3	Total bilirubin levels in HIV-1 infection	7.000000e-31
GCST002745_4	Total bilirubin levels in HIV-1 infection	2.000000e-09
GCST002745_5	Total bilirubin levels in HIV-1 infection	1.000000e-22
GCST002745_6	Total bilirubin levels in HIV-1 infection	7.000000e-12
GCST002745_7	Total bilirubin levels in HIV-1 infection	5.000000e-16
GCST002745_8	Total bilirubin levels in HIV-1 infection	4.000000e-16
GCST002745_9	Total bilirubin levels in HIV-1 infection	9.000000e-20
GCST003540_1	Clinical laboratory measurements	3.000000e-83
GCST009218_45	Lateral ventricle temporal horn volume	3.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004570	bilirubin measurement
EFO:0004725	metabolite measurement
EFO:0004297	clinical laboratory measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003414	Crigler-Najjar Syndrome	C16.320.565.300.281; C18.452.648.300.281
D005878	Gilbert Disease	C16.320.565.300.528; C18.452.648.300.528
D006932	Hyperbilirubinemia	C23.550.429
C536213	Crigler Najjar syndrome, type 2 (supp.)
C562692	Hyperbilirubinemia, Transient Familial Neonatal (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
UGT1A EXPRESSION	Ganetespib	Colorectal Cancer	Resistance	CIViC D	EID866

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

PharmGKB clinical annotations

8 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1042640	Other	3	acetaminophen
rs1042640	Toxicity	3	acetaminophen	Liver Failure;Acute
rs10929303	Other	3	acetaminophen
rs10929303	Toxicity	3	acetaminophen	Liver Failure;Acute
rs11563250	Metabolism/PK	3	bilirubin	Colorectal Neoplasms
rs11563250	Toxicity	3	irinotecan	Colorectal Neoplasms
rs8330	Other	3	acetaminophen
rs8330	Toxicity	3	acetaminophen	Liver Failure;Acute

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs8330	MROH2A, UGT1A, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9	3	1.75	3	acetaminophen;atazanavir;ritonavir
rs1042640	MROH2A, UGT1A, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9	3	2.25	3	acetaminophen;atazanavir;ritonavir
rs10929303	MROH2A, UGT1A, UGT1A1, UGT1A10, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9	3	1.75	3	acetaminophen;atazanavir;ritonavir
rs11563250	MROH2A, UGT1A	3	3.75	2	bilirubin;irinotecan

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
3,4,8-trimethylimidazo(4,5-f)quinoxalin-2-amine	affects response to substance	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	affects response to substance	1
calphostin C	increases degradation	1
2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases glucuronidation	1
Irinotecan	affects response to substance, increases response to substance	1
Carbamazepine	increases expression	1
Curcumin	decreases activity, increases degradation	1
Silymarin	decreases activity	1
beta-Naphthoflavone	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00288600	PHASE4	COMPLETED	Efficacy of High-dose Intravenous Immunoglobulin Therapy for Hyperbilirubinemia Due Rh Hemolytic Disease
NCT00360204	PHASE3	COMPLETED	Improving Health Outcomes for New Mothers and Babies
NCT00653874	PHASE3	COMPLETED	Transcutaneous Bilirubinometry in Healthy Term and Near-Term Neonates
NCT00004381	PHASE2	COMPLETED	Phase II Randomized Study of Tin Mesoporphyrin for Neonatal Hyperbilirubinemia
NCT00004382	PHASE2	COMPLETED	Phase II Study of Tin Mesoporphyrin vs Phototherapy for Hyperbilirubinemia in Premature Newborns
NCT00115544	PHASE2	COMPLETED	Safety and Pharmacology of Stanate
NCT03564678	PHASE2	TERMINATED	Levocarnitine and Vitamin B Complex in Treating PEG-Asparaginase or Inotuzumab Ozogamicin-Induced Hyperbilirubinemia in Patients With Acute Lymphoblastic Leukemia
NCT06518005	PHASE2	RECRUITING	Efficacy and Safety of GNT0003 Following Imlifidase Pre-treatment in Severe Crigler-Najjar Syndrome
NCT03223194	PHASE1	TERMINATED	Gene Transfer Clinical Study in Crigler-Najjar Syndrome
NCT06336369	Not specified	RECRUITING	Brown Adipose Tissue Activity in Gilbert’s Syndrome
NCT01550627	EARLY_PHASE1	COMPLETED	Effect of Intravenous Fluid Supplementation on Serum Bilirubin and Cardiorespiratory Parameters in Preterm Infants During Phototherapy
NCT00076960	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Stanate (TM) [Stannsoporfin]
NCT00383318	Not specified	COMPLETED	Demographic, Metabolic, and Genomic Description of Neonates With Severe Hyperbilirubinemia
NCT00635375	Not specified	COMPLETED	Comparative Study of Phototherapy for Hyperbilirubinemia
NCT00741117	Not specified	TERMINATED	Conjugated Hyperbilirubinemia and Pulse Oximetry
NCT01136577	Not specified	TERMINATED	Light-emitting Diodes (LED) Phototherapy for Hyperbilirubinemia of Term Newborn
NCT01622699	Not specified	COMPLETED	Implementation of a Transcutaneous Bilirubinometer
NCT01746511	Not specified	COMPLETED	Glycerin Suppositories to Reduce Jaundice in Premature Infants
NCT01944696	Not specified	UNKNOWN	Cycled Phototherapy: A Safer Effective Treatment for Small Premature Infants?
NCT02446951	Not specified	COMPLETED	Implementation of a Clinical Decision Rule for Treatment of Neonatal Jaundice in the Emergency Department
NCT02612207	Not specified	COMPLETED	Point-of-Care System for Determination of Bilirubin Capacity in Neonates
NCT02613676	Not specified	COMPLETED	Transcutaneous Screening for Risk of Severe Hyperbilirubinemia in South African Newborns
NCT02685189	Not specified	TERMINATED	Long-Term Clinical Follow-Up of Children Enrolled in Stannsoporfin Clinical Trial Protocol No. 64,185-06-2(W)
NCT02691156	Not specified	COMPLETED	Bilirubin Binding Capacity to Assess Bilirubin Load in Preterm Infants
NCT02712138	Not specified	WITHDRAWN	Biomarker for Gilbert Disease (BioGilbert)
NCT02774434	Not specified	COMPLETED	Efficacy Study of the Draeger Jaundice Meter (JM-105) in Neonates of ≥ 24 Weeks of Gestational Age
NCT02805296	Not specified	COMPLETED	High Intensity Phototherapy: Double vs. Single
NCT03195998	Not specified	COMPLETED	Validity of Transcutaneous Bilirubin Monitoring in Preterm Infants
NCT04271098	Not specified	COMPLETED	The Investigation of the Causes of Hepatic Dysfunction in the Postoperative Period During Open-heart Surgeries
NCT04897113	Not specified	UNKNOWN	Study of Efficacy and Safety of the Plasmapheresis Method With Albumin Compensation Compared With the Plasmapheresis Method Without Albumin Compensation for Aging Biomarkers Correction in Men and Women Aged 40 to 55 Years Old
NCT06421844	Not specified	RECRUITING	A Prospective Study: Smart Phone Application for Measure Serum Bilirubin Through Sclera Images
NCT07098234	Not specified	COMPLETED	Effect of Vitamin-D as an Adjuvant to Phototherapy in Reduction of Indirect Serum Bilirubin
NCT07409194	Not specified	ENROLLING_BY_INVITATION	The Effect of Acupressure on Hyperbilirubinemia in Newborns: A Randomized Controlled Trial
NCT01765283	PHASE1/PHASE2	COMPLETED	Safety Study of HepaStem for the Treatment of Urea Cycle Disorders (UCD) and Crigler-Najjar Syndrome (CN)
NCT06641154	PHASE1/PHASE2	RECRUITING	Gene Therapy for Crigler Najjar Syndrome Type I (AlphaCN)
NCT00461799	Not specified	COMPLETED	Orlistat Treatment of Crigler-Najjar Disease
NCT02051049	Not specified	COMPLETED	Long-term Safety Follow-up Study of Patients Having Received HepaStem (SAF001)
NCT02302690	Not specified	COMPLETED	Immunity Against AAV in Crigler Najjar Patient
NCT02356978	Not specified	UNKNOWN	New Phototherapy Device to Treat Patients With Crigler-Najjar Disease
NCT03078881	Not specified	COMPLETED	Clinical Assessment Study in Crigler-Najjar Syndrome