| Literature DB >> 27564568 |
C Liu1, W Yang1, D Pei2, C Cheng2, C Smith1, W Landier3, L Hageman3, Y Chen3, J J Yang1, K R Crews1, N Kornegay1, S E Karol4, F L Wong5, S Jeha4, J T Sandlund4, R C Ribeiro4, J E Rubnitz4, M L Metzger4, C-H Pui4, W E Evans1, S Bhatia3, M V Relling1.
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.Entities:
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Year: 2016 PMID： 27564568 PMCID： PMC5309133 DOI： 10.1002/cpt.463
Source DB: PubMed Journal: Clin Pharmacol Ther ISSN： 0009-9236 Impact factor: 6.875