title: Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies.
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.
authors: Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.|Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: R
authors: R
authors: Tamm
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: R
authors: R
authors: Mägi
authors: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany.
authors: R
authors: R
authors: Tremmel
authors: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany.
authors: S
authors: S
authors: Winter
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: E
authors: E
authors: Mihailov
authors: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors: A
authors: A
authors: Smid
authors: Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: A
authors: A
authors: Möricke
authors: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany.
authors: K
authors: K
authors: Klein
authors: Department of Pediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
authors: M
authors: M
authors: Schrappe
authors: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors: M
authors: M
authors: Stanulla
authors: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK.
authors: R
authors: R
authors: Houlston
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors: R
authors: R
authors: Weinshilboum
authors: Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors: Irena
authors: I
authors: Mlinarič Raščan
authors: Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.|Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: A
authors: A
authors: Metspalu
authors: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors: L
authors: L
authors: Milani
authors: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany.|Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany.|Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany.
authors: M
authors: M
authors: Schwab
authors: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany.
authors: E
authors: E
authors: Schaeffeler
mesh_terms: D000483:Alleles; D004957:Estonia; D055106:Genome-Wide Association Study; D006801:Humans; D008780:Methyltransferases / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D008780:Methyltransferases; C022745:thiopurine methyltransferase