TY - JOUR
T1 - Polymorphic variation in TPMT is the principal determinant of TPMT phenotype
T2 - A meta-analysis of three genome-wide association studies
AU - Tamm, R.
AU - Mägi, R.
AU - Tremmel, R.
AU - Winter, S.
AU - Mihailov, E.
AU - Smid, A.
AU - Möricke, A.
AU - Klein, K.
AU - Schrappe, M.
AU - Stanulla, M.
AU - Houlston, R.
AU - Weinshilboum, R.
AU - Mlinarič Raščan, Irena
AU - Metspalu, A.
AU - Milani, L.
AU - Schwab, M.
AU - Schaeffeler, E.
N1 - Funding Information:
The last two authors contributed equally to this work. We thank Britta Klumpp, Monika Elbl, Monika Seiler, Andrea Jarmuth, and Viljo Soo for excellent technical assistance. We thank Dr Krista Fischer for assistance with statistical analyses. We thank Ulrich M. Zanger for kindly providing liver tissue for TPMT analyses. We acknowledge the support of CeGaT GmbH, Tübingen, Germany, for next-generation sequencing. This work was supported by the Estonian Research Council (Grant IUT20-60), Estonian Science Foundation (ETF9293), the Robert Bosch Foundation (Stuttgart, Germany), the Federal Ministry for Education and Research (BMBF, Berlin, Germany, project “Virtual Liver” 0315755, LiSyM 031L0037), the Horizon 2020-PHC-2015 grant U-PGx 668353, the German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ, Heidelberg, Germany), the ICEPHA Graduate School Tuebingen-Stuttgart (Germany), and the United States National Institutes of Health (NIH) grants RO1 GM28157 and U19 GM61388.
Publisher Copyright:
© 2016 American Society for Clinical Pharmacology and Therapeutics
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
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U2 - 10.1002/cpt.540
DO - 10.1002/cpt.540
M3 - Article
C2 - 27770449
AN - SCOPUS:85011255970
SN - 0009-9236
VL - 101
SP - 684
EP - 695
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 5
ER -