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

Metabolism/PK

Genes

Haplotypes

Drugs

Specialty Population

PharmGKB ID

1184746746
AllelePhenotype
*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.
The level of evidence on this clinical annotation reflects the strength of the evidence base at the level of the gene and not at the level of individual alleles.

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.

Gene

TPMT

Phenotype Category

Metabolism/PK

Association Significance

The study does not report on the significance of this association

PharmGKB ID

1184516685

Study Parameters

Study type

cohort

Study size

3

Biogeographical group
More info on groups

European

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).

Gene

TPMT

Phenotype Category

Metabolism/PK

Association Significance

The study reports this association is significant

PharmGKB ID

1333193250

Study Parameters

1.

Study type

cohort

Study size

1135

Association p-value

< 0.0001

Allele frequency

*1=0.952

Biogeographical group
More info on groups

Multiple groups, White, Asian (Indian sub-continent), mixed, Black, Oriental, unknown

Population description

children (pediatrics)

Study Cohort: Mercaptopurine-TGNs

2.

Study type

cohort

Study size

1135

Association p-value

< 0.0001

Allele frequency

*1=0.952

Biogeographical group
More info on groups

Multiple groups, White, Asian (Indian sub-continent), mixed, Black, Oriental, unknown

Population description

children (pediatrics)

Study Cohort: Mercaptopurine-MeMPNs

3.

Study type

cohort

Study size

1135

Association p-value

= 0.0009

Allele frequency

*1=0.952

Biogeographical group
More info on groups

Multiple groups, White, Asian (Indian sub-continent), mixed, Black, Oriental, unknown

Population description

children (pediatrics)

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.

Gene

TPMT

Haplotype

TPMT*1, TPMT*32

Phenotype Category

Other

Association Significance

The study reports this association is not significant

PharmGKB ID

1444672801

Study Parameters

Study type

Study size

1

Biogeographical group
More info on groups

East Asian

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.

Gene

TPMT

Haplotype

TPMT*1, TPMT*27

Phenotype Category

Metabolism/PK

Association Significance

The study does not report on the significance of this association

PharmGKB ID

1184517715

Study Parameters

Study type

cohort

Study size

1

Biogeographical group
More info on groups

East Asian

Population description

women

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.

Gene

TPMT

Phenotype Category

Metabolism/PK

Association Significance

The study reports this association is significant

PharmGKB ID

1184467144

Study Parameters

1.

Study type

cohort

Association p-value

< 0.005

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

cohort

Association p-value

= 0.005

Population description

Study Cohort: artificial constructs - P-value given for the *3A, *5, *14, *18, *21, *22 alleles

3.

Study type

cohort

Association p-value

< 0.05

Population description

Study Cohort: artificial constructs - P-value given for the *9 and *19 alleles

History

No history available.