Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait

被引：34

作者：

Liu, C. ^{[1
]}

Yang, W. ^{[1
]}

Pei, D. ^{[2
]}

Cheng, C. ^{[2
]}

Smith, C. ^{[1
]}

Landier, W. ^{[3
]}

Hageman, L. ^{[3
]}

Chen, Y. ^{[3
]}

Yang, J. J. ^{[1
]}

Crews, K. R. ^{[1
]}

Kornegay, N. ^{[1
]}

Karol, S. E. ^{[4
]}

Wong, F. L. ^{[5
]}

Jeha, S. ^{[4
]}

Sandlund, J. T. ^{[4
]}

Ribeiro, R. C. ^{[4
]}

Rubnitz, J. E. ^{[4
]}

Metzger, M. L. ^{[4
]}

Pui, C-H ^{[4
]}

Evans, W. E. ^{[1
]}

Bhatia, S. ^{[3
]}

Relling, M. V. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA

[3] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA

[4] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA

[5] City Hope Natl Med Ctr, Dept Populat Sci, Duarte, CA USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2017年 / 101卷 / 03期

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; INFLAMMATORY-BOWEL-DISEASE; CHILDRENS-ONCOLOGY-GROUP; DRUG-METABOLISM GENES; S-METHYLTRANSFERASE; MERCAPTOPURINE INTOLERANCE; CAUCASIAN POPULATION; BLACK SUBJECTS; CHILDHOOD; POLYMORPHISM;

D O I：

10.1002/cpt.463

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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= 8.6x 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= 2.4x 10(-11)). Using 177 lymphoblastoid cell lines (LCLs), there were 251 SNPs ranked higher than the top TPMT SNP (rs1142345; P= 6.8x 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.

引用

页码：373 / 381

页数：9

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