1. Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait.
- Author
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Liu C, Yang W, Pei D, Cheng C, Smith C, Landier W, Hageman L, Chen Y, Yang JJ, Crews KR, Kornegay N, Karol SE, Wong FL, Jeha S, Sandlund JT, Ribeiro RC, Rubnitz JE, Metzger ML, Pui CH, Evans WE, Bhatia S, and Relling MV
- Subjects
- Antimetabolites, Antineoplastic administration & dosage, Child, Dose-Response Relationship, Drug, Female, Genome-Wide Association Study, Genotype, Humans, Male, Mercaptopurine administration & dosage, Pharmacogenetics, Polymorphism, Single Nucleotide, Antimetabolites, Antineoplastic pharmacokinetics, Leukemia drug therapy, Mercaptopurine pharmacokinetics, Methyltransferases genetics
- 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., Competing Interests: MVR and WEE: Prometheus Labs - Royalties from licensing TPMT genotyping., (© 2016 American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2017
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