Assess risk, due to genetics, for severe myelosuppression with standard dosing of thiopurine drugs. Appropriate for pre- or post-therapeutic assessments. Preferred test for patients with recent heterologous blood transfusion. Can be performed irrespective of thiopurine therapy.
- Patient Preparation
- Lavender (EDTA), pink (K2EDTA), or yellow (ACD Solution A or B).
- Specimen Preparation
- Transport 3 mL whole blood. (Min: 1 mL)
- Storage/Transport Temperature
- Unacceptable Conditions
- Plasma or serum. Heparinized specimens.
- Ambient: 72 hours; Refrigerated: 2 weeks; Frozen: 1 month.
Characteristics:Thiopurine therapy is used in the treatment of autoimmune diseases, inflammatory bowel disease and acute lymphoblastic leukemia and is also used to prevent rejection after solid organ transplant. Thiopurine drugs (eg, Azathioprine, 6-mercaptopurine, 6-thioguanine) are antimetabolites and must be metabolized to 6-thioguanine nucleotides (6-TGN) for activity. The inactivation of thiopurine drugs is primarily catalyzed by TPMT. Variants in the TPMT gene can lead to low TPMT enzyme activity, resulting in accumulation of cytotoxic metabolites and increased risk for drug-related myelotoxicity with standard doses of thiopurine drugs.
Incidence of TPMT deficiency: In the general population,approximately 0.3 percent of individuals have low TPMT activity and 10 percent have intermediate TPMT activity.
TPMT *2: African 0.000792, Asian 0.0, Caucasian 0.00190, Mediterranean 0.00408, Mexican 0.00592, Middle Eastern 0.00749
TPMT *3A: African 0.00198, Asian 0.0001118, Caucasian 0.0356, Mediterranean 0.0254, Mexican 0.0533, Middle Eastern 0.0114
TPMT *3B: African 0.0, Asian 0.0, Caucasian 0.000461, Mediterranean 0.00426, Mexican 0.00690, Middle Eastern 0.00562
TPMT *3C: African 0.0495, Asian 0.0157, Caucasian 0.004205, Mediterranean 0.00545, Mexican 0.00888, Middle Eastern 0.00562
Inheritance: Autosomal co-dominant.
Cause: TPMT gene variants resulting in enzyme deficiency.
Variants Tested:TPMT deficiency alleles: *2 (c.238G>C; p.Ala80Pro), *3A (c.[460G>A;719A>G]; p.[Ala154Thr;Tyr240Cys]), *3B (c.460G>A; p.Ala154Thr), *3C (c.719A>G; p.Tyr240Cys).
No variants detected is predictive of *1 functional alleles and normal TPMT enzyme activity.
(Variants are numbered according to NM_000367 transcript)
Clinical Sensitivity: 95 percent.
Methodology: Polymerase chain reaction(PCR) and fluorescence monitoring.
Analytical Sensitivity and Specificity: 99 percent.
Limitations: Only the targeted TPMT variants will be detected by this panel. Because the complex *3A allele contains the variants found in the *3B and *3C alleles, this test cannot distinguish the 3A/Negative genotype (intermediate enzyme activity) from the rare *3B/*3C genotype (no or low enzyme activity). This test does not assess for TPMT variants associated with ultra-high enzyme activity. Genotyping will reflect donor status in patients who have received allogenic stem cell or bone marrow transplants. TPMT enzyme activity, drug metabolism and risk for adverse reactions to thiopurines may be affected by additional genetic and non-genetic factors not evaluated by this test. Diagnostic errors can occur due to rare sequence variations. Genotyping does not replace the need for therapeutic drug monitoring and clinical observation.
Counseling and informed consent are recommended for genetic testing. Consent forms are available online at www.aruplab.com.
|Component Test Code*||Component Chart Name||LOINC|
|2012238||TPMT Genotype Specimen||31208-2|
|2012240||TPMT Predicted Phenotype||36922-3|
- AZA toxicity
- S-adenosyl-L-methionine genotype
- Thiopurine S-methyltransferase genotype
- TPMT genetics
- TPMT mutation