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The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for capecitabine (a fluorouracil prodrug) based on DPYD genotype (PMID:21412232). They recommend that an alternate drug be used for poor metabolizer patients, and a reduced dose or alternate drug for intermediate metabolizer patients.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles, 2 decreased activity alleles, or one inactive and one decreased activity alleles) | Select alterantive drug. Tegafur is not a suitable alternative because this drug is also metabolized by DPD. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression. |
| IM (1 active allele and 1 inactive or decreased activity allele) | Reduce dose by 50% or select alternative drug. Tegafur is not a suitable alternative because this drug is also a substrate for DPD. Increase dose in response to toxicity and efficacy. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression. |
| Allele Type | Alleles |
|---|---|
| active | *1, *4, *5, *6, *9A |
| decreased activity | *9B, *10 |
| inactive | *2A, *3, *7, *8, *11, *12, *13, 496A>G, IVS10-15T>C, 1156G>T, 1845G>T |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for fluorouracil based on DPYD genotype (PMID:21412232). They recommend that an alternate drug be used for poor metabolizer patients, and a reduced dose or alternate drug for intermediate metabolizer patients.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles, 2 decreased activity alleles, or one inactive and one decreased activity alleles) | Select alterantive drug. Tegafur is not a suitable alternative because this drug is also metabolized by DPD. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression. |
| IM (1 active allele and 1 inactive or decreased activity allele) | Reduce dose by 50% or select alternative drug. Tegafur is not a suitable alternative because this drug is also a substrate for DPD. Increase dose in response to toxicity and efficacy. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression. |
| Allele Type | Alleles |
|---|---|
| active | *1, *4, *5, *6, *9A |
| decreased activity | *9B, *10 |
| inactive | *2A, *3, *7, *8, *11, *12, *13, 496A>G, IVS10-15T>C, 1156G>T, 1845G>T |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tegafur/uracil combination based on DPYD genotype (PMID:21412232). They recommend that an alternate drug be used for poor metabolizer patients, but do not provide a recommendation for intermediate metabolizer patients.
| Phenotype (Genotype) | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| PM (2 inactive alleles, 2 decreased activity alleles, or one inactive and one decreased activity alleles) | Select alterantive drug. Fluorouracil or capecitabine are not suitable alternatives because both are also metabolized by DPD. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS). Kinetic effect (NS). |
| IM (1 active allele and 1 inactive or decreased activity allele) | None. | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS). Kinetic effect (NS). |
| Allele Type | Alleles |
|---|---|
| active | *1, *4, *5, *6, *9A |
| decreased activity | *9B, *10 |
| inactive | *2A, *3, *7, *8, *11, *12, *13, 496A>G, IVS10-15T>C, 1156G>T, 1845G>T |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- NS: not statistically significant difference.
Information regarding PGx on FDA drug labels is derived from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels". Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.
The FDA recommends, but does not require, genetic testing prior to initiating treatment with capecitabine.
Capecitabine is a pro-drug of 5-fluorouracil used for the treatment of various types of neoplasms including colorectal and breast neoplasms. Variants in the DPYD gene (also known as dihydropyrimidine dehydrogenase and DPD) are associated with increased risk for adverse events. See the Fluroropyrimidine Pathway and DPYD VIP for more information.
Excerpts from the capecitabine (Xeloda) drug label:
Capecitabine "is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency."
"Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded."
The label also notes drug-drug interactions with warfarin and phenytoin and cautions that "care should be exercised when XELODA is coadministered with CYP2C9 substrates."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Capecitabine drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
The FDA recommends, but does not require, genetic testing prior to initiating treatment with fluorouracil (Efudex).
Fluorouracil is used for the treatment of various types of neoplasms including colorectal neoplasms. Variants in the DPYD gene (also known as dihydropyrimidine dehydrogenase and DPD) are associated with increased risk for adverse events. See the Fluroropyrimidine Pathway and DPYD VIP for more information.
Excerpts from the fluorouracil (Efudex) drug label:
"Efudex should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities."
"Rarely, life-threatening toxicities such as stomatitis, diarrhea, neutropenia, and neurotoxicity have been reported with intravenous administration of fluorouracil in patients with DPD enzyme deficiency. One case of life-threatening systemic toxicity has been reported with the topical use of Efudex in a patient with DPD enzyme deficiency. Symptoms included severe abdominal pain, bloody diarrhea, vomiting, fever, and chills. Physical examination revealed stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, inflammation of the esophagus, stomach, and small bowel. Although this case was observed with 5% fluorouracil cream, it is unknown whether patients with profound DPD enzyme deficiency would develop systemic toxicity with lower concentrations of topically applied fluorouracil."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Fluorouracil drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below. Please follow the link in the "Position" column for more information about a particular variant. Each link in the "Position" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.
| Position ? | Drug ? | Relevance ? |
Strength of Evidence ? |
|---|---|---|---|
| rs3918290 |
To see relevance please register or sign in. |
1 |
Download a summary of all Clinical Annotations available.
Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.
The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.
A non-comprehensive list of genetic tests for specific variants, including descriptions of and links to individual tests; manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.
The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.
The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.
Links in the "Drugs" column lead to PharmGKB Drug Pages.
|
Variant?
(build 132) |
Alternate Names ? | Drugs ? |
Alleles
?
(+ chr strand) |
Function ? |
Amino Acid?
Translation |
|
|---|---|---|---|---|---|---|
| rs17116806 |
C > A
|
Not Available | ||||
| rs17376848 | 1896T>C, Phe632Phe |
A > G
|
Not Available |
Phe632Phe
|
||
| rs1760217 |
A > G
|
Not Available | ||||
| rs1801158 | c.1601G>A, g.410195G>A, g.67953339C>T, p.Ser534Asn |
C > T
|
Missense |
Ser534Asn
|
||
| rs1801159 | DPYD*5, DPYD:A1627G, DPYD:I543V, c.1627A>G, g.410221A>G, g.67953313T>C, p.Ile543Val |
T > C
|
Missense |
Ile543Val
|
||
| rs1801160 | 2194G>A, c.2194G>A, g.620696G>A, g.67742838C>T, p.Val732Ile |
C > T
|
Missense |
Val732Ile
|
||
| rs1801265 | DPYD*9A, DPYD:C29R, DYPD:T85C, c.85C>T, c.85T>C, g.42731C>T, g.42731T>C, g.68320803G>A, g.98121473G>A, p.Cys29Arg |
G > A
|
Missense |
Cys29Arg
|
||
| rs2297595 | DPYD:496A>G, DPYD:Met166Val, c.496A>G, g.226525A>G, g.68137009T>C, p.Met166Val |
T > C
|
Missense |
Met166Val
|
||
| rs3918290 | DPYD*2A, DPYD:67887533 G>A, DPYD:IVS14 + 1G>A, c.1905+1G>A, g.476002G>A, g.67887532C>T |
C > T
|
Not Available | |||
| rs45589337 |
T > C
|
Missense |
Lys259Glu
|
|||
| rs4970722 |
A > T
|
Not Available | ||||
| rs55886062 | c.1679T>A, g.410273T>A, g.67953261A>T, p.Ile560Asn |
A > T
A > C
|
Missense |
Ile560Asn
|
||
| rs56038477 | 1236G>A |
C > T
|
Not Available |
Glu412Glu
|
||
| rs67376798 | 2846A>T, c.2846A>T, g.67519865T>A, g.843669A>T, p.Asp949Val |
T > A
|
Missense |
Asp949Val
|
Overview
| Alternate Names: | OTTHUMP00000037640; OTTHUMP00000058954; dihydropyrimidine dehydrogenase [NADP+]; dihydrothymine dehydrogenase; dihydrouracil dehydrogenase |
|---|---|
| Alternate Symbols: | DHP; DHPDHASE; DPD; MGC132008; MGC70799 |
| Haplotypes: | DPYD*1; DPYD*2A; DPYD*2B; DPYD*3; DPYD*4; DPYD*5; DPYD*6; DPYD*7; DPYD*8; DPYD*9A; DPYD*9B; DPYD*10; DPYD*11; DPYD*12; DPYD*13 |
| PharmGKB Accession Id: | PA145 |
Details
| Cytogenetic Location: | chr1 : p21.3 - p21.3 |
|---|---|
| GP mRNA Boundary†: | chr1 : 97543299 - 98386615 |
| GP Gene Boundary†: | chr1 : 97540299 - 98396615 |
| Strand: | minus |
| Product Name: | No data available |
All alleles are displayed on the positive chromosomal strand.
| Haplotype | rs147545709 | rs1801158 | rs1801159 | rs1801160 | rs1801265 | rs1801266 | rs1801268 | rs3918290 | rs55886062 | rs72549303 | rs72549306 | rs72549309 | rs78060119 | rs80081766 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DPYD*1 | C | C | T | C | A | G | C | C | A | G | C | A | C | C |
| DPYD*2A | C | C | T | C | A | G | C | T | A | G | C | A | C | C |
| DPYD*2B | C | C | C | C | A | G | C | T | A | G | C | A | C | C |
| DPYD*3 | C | C | T | C | A | G | C | C | A | del | C | A | C | C |
| DPYD*4 | C | T | T | C | A | G | C | C | A | G | C | A | C | C |
| DPYD*5 | C | C | C | C | A | G | C | C | A | G | C | A | C | C |
| DPYD*6 | C | C | T | T | A | G | C | C | A | G | C | A | C | C |
| DPYD*7 | C | C | T | C | A | G | C | C | A | G | C | del | C | C |
| DPYD*8 | C | C | T | C | A | A | C | C | A | G | C | A | C | C |
| DPYD*9A | C | C | T | C | G | G | C | C | A | G | C | A | C | C |
| DPYD*9B | T | C | T | C | G | G | C | C | A | G | C | A | C | C |
| DPYD*10 | C | C | T | C | A | G | A | C | A | G | C | A | C | C |
| DPYD*11 | C | C | T | C | A | G | C | C | A | G | A | A | C | C |
| DPYD*12 | C | C | T | C | A | G | C | C | A | G | C | A | A | T |
| DPYD*13 | C | C | T | C | A | G | C | C | C | G | C | A | C | C |
PharmGKB Curated Pathways
Pathways created internally by PharmGKB based primarily on literature evidence.
-
Fluoropyrimidine Pathway, Pharmacokinetics
Representation of the metabolic pathways for fluoropyrimidines.
External Pathways
Links to non-PharmGKB pathways.
Curated Information ?
| Evidence | Drug |
|---|---|
| bevacizumab | |
| capecitabine | |
| cetuximab | |
| cyanocobalamin | |
| cyclophosphamide | |
| fluorouracil | |
| leucovorin | |
| methotrexate | |
| mitomycin | |
| oxaliplatin | |
| raltitrexed | |
| tegafur |
| Evidence | Drug Class |
|---|---|
| Pyrimidine analogues |
Curated Information ?
Publications related to DPYD: 79
LinkOuts
- Entrez Gene:
- 1806
- OMIM:
- 274270
- 612779
- UCSC Genome Browser:
- NM_000110
- RefSeq RNA:
- NM_000110
- NM_001160301
- RefSeq Protein:
- NP_000101
- NP_001153773
- RefSeq DNA:
- AC_000044
- AC_000133
- NC_000001
- NG_008807
- NT_032977
- NW_001838589
- NW_921795
- UniProtKB:
- DPYD_HUMAN (Q12882)
- Q96HL6_HUMAN (Q96HL6)
- Ensembl:
- ENSG00000188641
- GenAtlas:
- DPYD
- GeneCard:
- GC01M097543 (1806)
- MutDB:
- DPYD
- ALFRED:
- LO003560O