Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait

We performed a genome-wide association study of primary erythrocyte TPMT activity in children with leukemia (n = 1026). Adjusting for age and ancestry, TPMT was the only gene that reached genome-wide significance (top hit rs1142345 or 719A>G, P = 8.6 × 10−61). Additional genetic variants (besides the 3 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 251251 SNPs ranked higher than the top TPMT SNP (rs1142345 P = 6.8 × 10−5), showing the 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. This article is protected by copyright. All rights reserved.