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Comprehensive study...
Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden
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- Zimdahl Kahlin, Anna (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten
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- Helander, Sara (author)
- Linköpings universitet,Avdelningen för klinisk kemi,Medicinska fakulteten
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- Skoglund, Karin (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Region Östergötland, Verksamhetsutveckling vård och hälsa
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- Söderkvist, Peter, 1953- (author)
- Linköpings universitet,Avdelningen för cellbiologi,Medicinska fakulteten,Region Östergötland, Klinisk genetik
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- Mårtensson, Lars-Göran (author)
- Linköpings universitet,Kemi,Tekniska fakulteten
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- Lindqvist Appell, Malin (author)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten
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(creator_code:org_t)
- PERGAMON-ELSEVIER SCIENCE LTD, 2019
- 2019
- English.
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In: Biochemical Pharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0006-2952 .- 1356-1839. ; 164, s. 263-272
- Related links:
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https://liu.diva-por... (primary) (Raw object)
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http://liu.diva-port...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patients TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Keyword
- Thiopurine; TPMT; Pharmacogenetics; Genotyping; Individualization
Publication and Content Type
- ref (subject category)
- art (subject category)
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