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Overview
| Alternate Names: | UDP glucuronosyltransferase 1A1; UDP glycosyltransferase 1 family, polypeptide A1; bilirubin UDP-glucuronosyltransferase 1-1; bilirubin UDP-glucuronosyltransferase isozyme 1 |
|---|---|
| Alternate Symbols: | GNT1; HUG-BR1; UDPGT; UGT1; UGT1*1; UGT1A; UGT1A5 |
| PharmGKB Accession Id: | PA420 |
Details
| Cytogenetic Location: | chr2 : q37.1 |
|---|---|
| GP mRNA Boundary†: | chr2 : 234333658 - 234346684 |
| GP Gene Boundary†: | chr2 : 234323658 - 234349684 |
| Strand: | plus |
| Product Name: | UDP glucuronosyltransferase 1A1, UDP glycosyltransferase 1 family, polypeptide A1, UDP glycosyltransferase 1 family, polypeptide A1 precursor, bilirubin UDP-glucuronosyltransferase 1-1, bilirubin UDP-glucuronosyltransferase isozyme 1 |
Introduction
UGT1A1 is one of 9 isozymes encoded by the UGT1A locus, a superfamily of Phase II drug metabolizing enzymes that catalyze the glucuronidation reaction to render xenobiotic and endogenous compounds to water soluble molecules that can be excreted. Located on chromosome 2q37 [PMID: 8467709], UGT1A1 is the most 3' of the UGT1A isoforms, consisting of a unique promoter and exon 1 that are preferentially spliced to a set of common exons (2-5). The resulting product is a unique 2342 base pair sequence encoding a 533 amino acid protein [PMID: 1339448]. Expressed hepatically as well as extrahepatically (colon, intestine, stomach) [PMID: 10836148], its primary function is in the liver, where it is the sole enzyme responsible for bilirubin metabolism and is involved in the metabolism of many other endogenous compounds (estrogens, thyroid hormone) as well as xenobiotic compounds such as irinotecan [PMID: 9466980], etoposide [PMID: 12969965] and tranilast [PMID: 14647407].
The promoter region and exon 1 of UGT1A1 contain the most common polymorphisms: an insertion/deletion of (TA)6/(TA)7 (UGT1A1*28) and a non-synonymous coding variant G71R (UGT1A1*6), respectively. The UGT1A1*28 allele is common in Caucasian populations and populations of African origin (0.26-0.56) [PMID: 10591539] and defines the genetic basis of Gilbert syndrome. The UGT1A1*6 variant is found almost exclusively in Asian populations, with a frequency of 0.13-0.25 [PMID: 9784835]. UGT1A1*6 can also cause the phenotype of hyperbilirubinemia [PMID: 9630669]. The UGT1A1*28 and *6 variants are known to reduce enzymatic activity of UGT1A1, and have been associated with increased risk of adverse outcome and severe toxicity during irinotecan treatment [PMID: 11990381, 12485959]. Further studies have identified additional UGT1A1 variants that may also be associated with the prevalence of severe toxicity observed during irinotecan treatment [PMID: 15007088, 12464801].
In-Depth Annotations (
)
-
rs4124874
at chr2:234330398
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
*60 is a common variant of UGT1A1. It is located in the Phenobarbital Response Enhancer Module (an upstream regulatory sequence) and may be involved in irinotecan response and in Gilbert syndrome.- Variant Name:
- UGT1A1*60;UGT1A1:-3279T>G;UGT1A1:-3263T>G
- Related Drugs:
- irinotecan
- Related Diseases:
- Gilbert's syndrome
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp
-
rs10929302
at chr2:234330521
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
*93 is a common variant of UGT1A1 in Caucasian and African-American populations. It is located in the Phenobarbital Response Enhancer Module (an upstream regulatory sequence) and may be important in predicting irinotecan response.- Variant Name:
- UGT1A1*93;UGT1A1:-3156G>A
- Related Drugs:
- irinotecan
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp
-
rs4148323
at chr2:234333883
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
*6 is the most common UGT1A1 coding variant found in Asians. It may result in reduced capacity to metabolize irinotecan and hence irinotecan toxicity.- Variant Name:
- UGT1A1*6;UGT1A1:211G>A;UGT1A1:Gly71Arg
- Related Drugs:
- irinotecan
- Related Diseases:
- Gilbert's syndrome
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp
-
rs35350960
at chr2:234334358
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
The *27 variant form of UGT1A1 has very low activity in vitro, so is likely to be important in irinotecan response in vivo. It may also be important in Gilbert syndrome.- Variant Name:
- UGT1A1*27;UGT1A1:Pro229Glu
- Related Drugs:
- irinotecan
- Related Diseases:
- Gilbert's syndrome
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp
Curated Annotations (
)
-
rs4124874
at chr2:234330398
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
Associated with hyperbilirubinemia in Japanese.- Variant Name:
- UGT1A1*60; UGT1A1:-3279T>G
- Evidence:
-
PMID:11906189
-
rs10929302
at chr2:234330521
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
May be an significant predictor of absolute neurophil count (ANC) after irinotecan treatment, associated with severe neutopenia; -3156G carriers tend to have a lower level of total bilirubin.- Variant Name:
- UGT1A1:G-3156A
- Evidence:
-
PMID:15007088
-
rs887829
at chr2:234333309
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
This variant is in the promoter region of UGT1A1 and associated with serum bilirubin levels and hyperbilirubinemia in a genome wide association scan from 4300 Sardinian individuals.- Related Diseases:
- Hyperbilirubinemia
- Evidence:
-
PMID:19419973
-
rs8175347
at chr2:234333620
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
Risk or phenotype-associated allele: (TA)7 repeat insertion in the UGT1A1 promoter. Phenotype: Patients with the UGT1A1*28 7/7 genotype had a statistically greater baseline total bilirubin than patients with homozygous (6-TA repeat) 6/6 or heterozygous 6/7 genotype (p = 0.005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (p > 0.2) or diarrhea (p > 0.1). However, patients with the *28 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38-glucuronide to SN-38 AUC ratios. Study size: 74. Study population/ethnicity: Pediatric patients from five institutional clinical trials with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks). Significance metric(s): p = 0.005 - 0.2. Type of association: GN; PK; PD.- Variant Name:
- UGT1A1*28, 7-TA insertion in promoter, short tandem repeat (microsatellite) (TA)7
- Related Drugs:
- irinotecan, SN-38
- Related Diseases:
- Drug Toxicity, Neoplasms
- Evidence:
-
PMID:17577039
-
rs8175347
at chr2:234333620
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
Risk or phenotype-associated allele: TA repeat insertion in UGT1A1 promoter, TA(7). Phenotype: There was no significant association between systemic exposure of tipifarnib (AUC levels) and UGT1A1*28 (promoter TA(7) repeat) genotype. Study size: 28 (16 male). Study population/ethnicity: Caucasian cancer patients, aged 34-75. Significance metric(s): Not significant, p = 0.79. Type of association: GN; PK- Variant Name:
- UGT1A1*28, 7-TA insertion in promoter, short tandem repeat (microsatellite) (TA)7
- Related Drugs:
- Tipifarnib
- Evidence:
-
PMID:15122075
-
rs4148323
at chr2:234333883
in
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
Associated with reduced AUC ratio of SN38G/SN38 in combination with *60 (*6/*60) or *28 (*6/*28) and associated with neutropenia in Japanese. UGT1A1*6 is more prevalent than UGT1A1*28 in asian population, thus especially important for irinotecan induced toxicity in asian. It is associated with Gilbert's syndrome among asians, Crigler-Najjar syndrome type II (CN-II) and transient familial neonatal hyperbilirubinemia. It is the most common coding variant in Asians.- Variant Name:
- UGT1A1*6; UGT1A1:G211A; UGT1A1: G71R
- Evidence:
-
PMID:15179404
PMID:15179405
PMID:17558305
PMID:9630669
PMID:9784835
-
rs28934877
at chr2:234341718
in
HEATR7B1,
UGT1A1,
UGT1A10,
UGT1A3,
UGT1A4,
UGT1A5,
UGT1A6,
UGT1A7,
UGT1A8,
UGT1A9
Associated with Gilbert's syndrome and CRIGLER-NAJJAR SYNDROME, TYPE II.- Variant Name:
- UGT1A1:ASN400ASP
- Evidence:
-
PMID:12402338
Curated Information
The following genes are in curated knowledge about this gene.
| Gene | Relationship | Evidence | |
|---|---|---|---|
|
NR1I2 |
|
Publications |
|
NR1I3 |
|
Publications |
|
|
NR3C1 |
|
Publications |
Non-Curated Information
A list of non-curated publications that mention this gene along with other genes is available.
PharmGKB Curated Pathways
Curated Information
The following drugs are in curated knowledge about this gene.
| Drug Class | Relationship | Evidence | |
|---|---|---|---|
|
|
artemisinin and derivatives |
|
Publications |
|
|
farnesyltransferase inhibitors |
|
Publications |
Non-Curated Information
A list of non-curated publications that mention this gene along with other drugs is available.
Curated Information
The following diseases are in curated knowledge about this gene.
Non-Curated Information
A list of non-curated publications that mention this gene along with other diseases is available.
Curated Phenotype Datasets
These datasets are sorted alphabetically by title.
- Pharmacogenetic Risk Factors for Osteonecrosis of the Hip Among Children With Leukemia
- CO
Submitted by Mary Relling, PharmD involving ABCB1, CYP3A4, CYP3A5, GSTM1, GSTP1, GSTT1, MTHFR, NR3C1, SLC19A1, TPMT, TYMS, UGT1A1, VDR, dexamethasone, methotrexate, prednisone, , Osteonecrosis and Precursor Cell Lymphoblastic Leukemia-Lymphoma - Pharmacokinetics of etoposide, catechol metabolite
- PK
Submitted by Mary Relling, PharmD involving ABCB1, CYP3A4, CYP3A5, GSTP1, UGT1A1, VDR, etoposide, and Precursor Cell Lymphoblastic Leukemia-Lymphoma - RNA expression in metabolite and transport genes
- FA
Submitted by Howard McLeod, PharmD involving ABCB1, ABCC1, ABCC2, ABCC3, ABCC4, ABCG2, ATM, ATR, BAK1, BAX, BCL2, BCL2L1, CCNA2, CCND1, CDA, CDC2, CDC25C, CDC37, CDC45L, CDK2, CDK4, CDKN1A, CDKN1B, CDKN2A, CES1, CES2, CYP3A4, CYP3A5, DCK, DDB1, DHFR, DPYD, DPYS, DRG1, DTYMK, DUT, E2F1, ECGF1, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, FASLG, FDXR, FPGS, GGH, GSTM1, GSTP1, HMGB1, MAP4, MLH1, MPO, MSH2, MSH6, MTHFR, NFKB1, NME1, NME2, NT5C, PARP1, POLB, POLH, PTGS1, PTGS2, RAD9A, RB1, RRM1, RRM2, SOD1, TDP1, TK1, TOP1, TOP2A, TP53, TUBB, TYMS, UCK2, UGT1A1, UMPS, UNG, UPB1, UPP1, XPA, XPC, XRCC1, and Colonic Neoplasms
Additional Datasets
These datasets are minimally curated and are sorted alphabetically by title.
Downloads
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LinkOuts
- Entrez Gene ID:
- 54658
- OMIM Accession:
- 143500
- 191740
- 218800
- 237900
- 606785
- UCSC Genome Browser ID:
- NM_000463
- Ref Seq NM Accession:
- NM_000463
- Ref Seq NP Accession:
- AAA61248
- AAA63195
- AAF01205
- AAG30424
- AAG43197
- AAI28415
- AAI28416
- AAK27223
- AAK31204
- AAR95637
- AAS99732
- ABC88474
- ABC96771
- BAA25600
- BAF83523
- EAW71053
- NP_000454
- P22309
- Q5DT03
- Q9BX76
- Q9H3F9
- Q9UK62
- Ref Seq NT Accession:
- AC_000045
- AC_000134
- NC_000002
- NG_002601
- NG_009254
- NT_005120
- NW_001838868
- NW_921618
- UniProtKB Accesssion:
- UD11_HUMAN (P22309)
- Ensembl ID:
- ENSG00000167165
- GenAtlas ID:
- UGT1A1
- GeneCard ID:
- UGT1A1
Common Searches
Non-Curated Publications
A list of non-curated publications that mention this gene is available.