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Clin Pharmacol Ther. 2017 May;101(5):684-695. doi: 10.1002/cpt.540. Epub 2017 Feb 1.

Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies.

Author information

1
Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
2
Estonian Genome Center, University of Tartu, Tartu, Estonia.
3
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany.
4
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
5
Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
6
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
7
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK.
8
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
9
Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany.
10
Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany.

Abstract

Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 × 10-8 ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 × 10-72 ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage.

PMID:
27770449
PMCID:
PMC5395320
DOI:
10.1002/cpt.540
[Indexed for MEDLINE]
Free PMC Article

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