Clinical Annotation for TPMT*1, TPMT*19, TPMT*20, TPMT*21, TPMT*22, TPMT*30, TPMT*32, TPMT*33, TPMT*34; thioguanine (level 3 Metabolism/PK)
Level of Evidence
Phenotype Category
Genes
Haplotypes
Drugs
Specialty Population
PharmGKB ID
| Allele | Phenotype |
|---|---|
| *1 Normal function More allele information | Patients with two copies of the TPMT*1 allele may have increased metabolism of thioguanine as compared to patients with two uncertain function or unknown function alleles or an uncertain function or unknown function in combination with a normal function allele. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
| *19 Uncertain function More allele information | Patients with two copies of the TPMT*19 allele or one copy of the *19 allele in combination with a normal function allele may have decreased metabolism of thioguanine as compared to patients with two normal function alleles. Note that this allele has been assigned as an uncertain function allele by CPIC. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
| *20 Uncertain function More allele information | Patients with two copies of the TPMT*20 allele or one copy of the *20 allele in combination with a normal function allele may have decreased metabolism of thioguanine as compared to patients with two normal function alleles. Note that this allele has been assigned as an uncertain function allele by CPIC. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
| *21 Uncertain function More allele information | Patients with two copies of the TPMT*21 allele or one copy of the *21 allele in combination with a normal function allele may have decreased metabolism of thioguanine as compared to patients with two normal function alleles. Note that this allele has been assigned as an uncertain function allele by CPIC. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
| *22 Uncertain function More allele information | Patients with two copies of the TPMT*22 allele or one copy of the *22 allele in combination with a normal function allele may have decreased metabolism of thioguanine as compared to patients with two normal function alleles. Note that this allele has been assigned as an uncertain function allele by CPIC. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
| *30 Unknown function More allele information | Patients with two copies of the TPMT*30 allele or one copy of the *30 allele in combination with a normal function allele may have decreased metabolism of thioguanine as compared to patients with two normal function alleles. Note that this allele has been assigned as an unknown function allele by CPIC. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
| *32 Uncertain function More allele information | Patients with two copies of the TPMT*32 allele or one copy of the *32 allele in combination with a normal function allele may have decreased metabolism of thioguanine as compared to patients with two normal function alleles. Note that this allele has been assigned as an uncertain function allele by CPIC. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
| *33 Uncertain function More allele information | Patients with two copies of the TPMT*33 allele or one copy of the *33 allele in combination with a normal function allele may have decreased metabolism of thioguanine as compared to patients with two normal function alleles. Note that this allele has been assigned as an uncertain function allele by CPIC. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
| *34 Uncertain function More allele information | Patients with two copies of the TPMT*34 allele or one copy of the *34 allele in combination with a normal function allele may have decreased metabolism of thioguanine as compared to patients with two normal function alleles. Note that this allele has been assigned as an uncertain function allele by CPIC. This annotation only covers the pharmacokinetic relationship between TPMT and thioguanine and does not include evidence about clinical outcomes. Other genetic and clinical factors may also influence thioguanine metabolism. |
Level of Evidence Calculation More information
- Total Score
- 0
- Score Breakdown
- Variant Annotations = 0
- Dosing Guideline Annotations = 0
- Drug Label Annotations = 0
- Level Modifiers
- Calculated Level from Score
- Level 3Learn more about Clinical Annotation Levels of Evidence(opens in new window)
Evidence
- 0 Dosing Guideline Annotations
- 0 Drug Label Annotations
- 5 Variant Annotations from 5 Publications
- 5 Positive association Variant Annotations
- 0 Negative association Variant Annotations
1. Annotation of TPMT haplotypes TPMT*1TPMT*20TPMT*21TPMT*22
TPMT *1/*20 + *1/*21 + *1/*22 are associated with decreased enzyme activity of TPMT when assayed with thioguanine.
Three individuals were discovered to have intermediate TPMT activity. Patients were taking thioguanine or azathioprine for various conditions. TPMT activity measured in RBC using HPLC. Intermediate TPMT activity defined as >2 and <= 22 nmol 6-MTG x Hb/g x 1/h. One patient was found to be heterozygous for *1/*20, another for *1/*21 and the last for *1/*22. *21 and *22 were novel alleles in this study. Note that the patients with the *1/*20 had a borderline intermediate activity phenotype (22 nmol 6-MTG...etc.). The authors noted that based on analyses, these three variants may affect TPMT protein function.
From Publication
Study Parameters
2. Annotation of TPMT haplotypes TPMT*1TPMT*2TPMT*3ATPMT*3CTPMT*9TPMT*21TPMT*32TPMT*33TPMT*34
TPMT *1/*2 + *1/*3A + *1/*3C + *1/*9 + *1/*21 + *1/*32 + *1/*33 + *1/*34 are associated with decreased activity of TPMT when treated with mercaptopurine or thioguanine as compared to TPMT *1/*1.
In children with acute lymphoblastic leukemia, those heterozygous for a TPMT variant allele had increased levels of thioguanine nucleotides (TGNs), and decreased levels of methylmercaptopurine nucleotides (MeMPNs), as compared to wild-type; this indicates reduced TPMT activity for these genotypes. n=425 taking thioguanine and n=707 taking mercaptopurine. Note that not all heterozygote genotypes appeared in both the thioguanine and mercaptopurine cohorts, see paper for details. Also, the authors note that within the mercaptopurine cohort, those with the *1/*3C genotype had borderline-significantly lower TGN and MeMPN concentrations as compared to those with the *1/*3A genotype, despite similar drug doses (p=0.05 and p=0.06, respectively).
From Publication
Gene
Phenotype Category
Association Significance
Specialty Population
PharmGKB ID
Score More info on scoring
Study Parameters
1.
Study type
Study size
Association p-value
Allele frequency
Biogeographical group More info on groups
Population description
Study Cohort: Mercaptopurine-TGNs
2.
Study type
Study size
Association p-value
Allele frequency
Biogeographical group More info on groups
Population description
Study Cohort: Mercaptopurine-MeMPNs
3.
Study type
Study size
Association p-value
Allele frequency
Biogeographical group More info on groups
Population description
Study Cohort: Thioguanine-TGNs
3. Annotation of TPMT haplotypes TPMT*1TPMT*32
TPMT *1/*32 is associated with increased concentrations of thioguanine.
One Korean pediatric patient with ALL was genotyped as *1/*32. Under 43 mg/m 2 (57% of standard dose) of mercaptopurine, the concentrations of 6-thioguanine (6-TGN) were 1257 pmol/8×10E8 RBC (therapeutic range; 235–450 pmol/8×10E8 RBC). BUT in this patient TPMT activity measured after 2 years of mercaptopurine therapy showed normal TPMT activity (17.9 U/ml RBC). The patient had not received an RBC transfusion at least 3 months before measuring the TPMT activity without a history of allogeneic stem transplantation.
From Publication
Gene
Phenotype Category
Association Significance
PharmGKB ID
Score More info on scoring
Study Parameters
4. Annotation of TPMT haplotypes TPMT*1TPMT*27
TPMT *1/*27 is associated with decreased enzyme activity of TPMT when assayed with thioguanine.
A 59 year old women who underwent renal transplantation was found to have low TPMT activity (19.8 nmol 6-MTG/g Hb/h, where "low activity" was <27 nmol 6-MTG/g Hb/h). She was found to have a novel allele *27. Western blot analysis showed the average level of TPMT*27 protein was ~17% that of wild-type protein. TPMT enzyme activity of *27 was ~7.6% that of wild-type allozyme. This reduction in activity and levels may be explained by degradation of the protein. The subject was genotyped as *1S/*27.
From Publication
Gene
Phenotype Category
Association Significance
PharmGKB ID
Score More info on scoring
Study Parameters
Study type
Study size
Biogeographical group More info on groups
Population description
5. Annotation of TPMT haplotypes TPMT*1TPMT*2TPMT*3ATPMT*3BTPMT*3CTPMT*5TPMT*6TPMT*7TPMT*9TPMT*10TPMT*12TPMT*14TPMT*17TPMT*18TPMT*19TPMT*20TPMT*21TPMT*22TPMT*23TPMT*30
TPMT *2 + *3A + *3B + *3C + *5 + *6 + *7 + *9 + *10 + *12 + *14 + *17 + *18 + *19 + *20 + *21 + *22 + *23 + *30 are associated with decreased enzyme activity of TPMT when assayed with thioguanine in COS-7 cells as compared to TPMT *1.
Alleles were grouped by PharmGKB.
From Publication
Gene
Haplotype
Phenotype Category
Association Significance
PharmGKB ID
Score More info on scoring
Study Parameters
1.
Study type
Association p-value
Population description
Study Cohort: artificial constructs - P-value given for the *2, *3C, *6, *7, *10, *12, *17, *20, *23, *30 alleles
2.
Study type
Association p-value
Population description
Study Cohort: artificial constructs - P-value given for the *3A, *5, *14, *18, *21, *22 alleles
3.
Study type
Association p-value
Population description
Study Cohort: artificial constructs - P-value given for the *9 and *19 alleles
History
No history available.