title: Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait.
abstract: We performed a genomewide association study (GWAS) of primary erythrocyte thiopurine S-methyltransferase (TPMT) activity in children with leukemia (n = 1,026). Adjusting for age and ancestry, TPMT was the only gene that reached genomewide significance (top hit rs1142345 or 719A>G; P = 8.6 × 10-61). Additional genetic variants (in addition to the three single-nucleotide polymorphisms [SNPs], rs1800462, rs1800460, and rs1142345, defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2.4 × 10-11). Using 177 lymphoblastoid cell lines (LCLs), there were 251 SNPs ranked higher than the top TPMT SNP (rs1142345; P = 6.8 × 10-5), revealing a limitation of LCLs for pharmacogenomic discovery. In a GWAS, TPMT activity in patients behaves as a monogenic trait, further bolstering the utility of TPMT genetic testing in the clinic.
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: C
authors: C
authors: Liu
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: W
authors: W
authors: Yang
authors: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: D
authors: D
authors: Pei
authors: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: C
authors: C
authors: Cheng
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: C
authors: C
authors: Smith
authors: School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: W
authors: W
authors: Landier
authors: School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: L
authors: L
authors: Hageman
authors: School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Y
authors: Y
authors: Chen
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: J J
authors: JJ
authors: Yang
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: K R
authors: KR
authors: Crews
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: N
authors: N
authors: Kornegay
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: S E
authors: SE
authors: Karol
authors: Department of Population Sciences, City of Hope, Duarte, California, USA.
authors: F L
authors: FL
authors: Wong
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: S
authors: S
authors: Jeha
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: J T
authors: JT
authors: Sandlund
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: R C
authors: RC
authors: Ribeiro
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: J E
authors: JE
authors: Rubnitz
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: M L
authors: ML
authors: Metzger
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: C-H
authors: CH
authors: Pui
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: W E
authors: WE
authors: Evans
authors: School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: S
authors: S
authors: Bhatia
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: M V
authors: MV
authors: Relling
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008780:Methyltransferases / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase