Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait

Overview

Journal Clin Pharmacol Ther

Publisher Wiley

Specialty Pharmacology

Date 2016 Aug 27

PMID 27564568

Citations 23

Authors

C Liu

W Yang

D Pei

C Cheng

C Smith

W Landier

L Hageman

Y Chen

J J Yang

K R Crews

N Kornegay

S E Karol

F L Wong

S Jeha

J T Sandlund

R C Ribeiro

J E Rubnitz

M L Metzger

C-H Pui

W E Evans

S Bhatia

M V Relling

Affiliations

Soon will be listed here.

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

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References

Stocco G, Yang W, Crews K, Thierfelder W, Decorti G, Londero M . PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. Hum Mol Genet. 2012; 21(21):4793-804. PMC: 3471396. DOI: 10.1093/hmg/dds302. View

Marshall E . Preventing toxicity with a gene test. Science. 2003; 302(5645):588-90. DOI: 10.1126/science.302.5645.588. View

Serpe L, Calvo P, Muntoni E, DAntico S, Giaccone M, Avagnina A . Thiopurine S-methyltransferase pharmacogenetics in a large-scale healthy Italian-Caucasian population: differences in enzyme activity. Pharmacogenomics. 2009; 10(11):1753-65. DOI: 10.2217/pgs.09.103. View

Keller L, Xu W, Wang H, Winblad B, Fratiglioni L, Graff C . The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J Alzheimers Dis. 2010; 23(3):461-9. DOI: 10.3233/JAD-2010-101068. View

McLeod H, Coulthard S, THOMAS A, Pritchard S, King D, Richards S . Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol. 1999; 105(3):696-700. DOI: 10.1046/j.1365-2141.1999.01416.x. View

Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Iven H . Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther. 1997; 62(1):60-73. DOI: 10.1016/S0009-9236(97)90152-1. View

Cooper S, Ford L, Berg J, Lewis M . Ethnic variation of thiopurine S-methyltransferase activity: a large, prospective population study. Pharmacogenomics. 2008; 9(3):303-9. DOI: 10.2217/14622416.9.3.303. View

Jones C, Smart C, Titus A, Blyden G, Dorvil M, Nwadike N . Thiopurine methyltransferase activity in a sample population of black subjects in Florida. Clin Pharmacol Ther. 1993; 53(3):348-53. DOI: 10.1038/clpt.1993.31. View

Relling M, Hancock M, Rivera G, Sandlund J, Ribeiro R, Krynetski E . Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999; 91(23):2001-8. DOI: 10.1093/jnci/91.23.2001. View

10.

Relling M, Pui C, Cheng C, Evans W . Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood. 2006; 107(2):843-4. DOI: 10.1182/blood-2005-08-3379. View

11.

Frayling T, Timpson N, Weedon M, Zeggini E, Freathy R, Lindgren C . A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007; 316(5826):889-94. PMC: 2646098. DOI: 10.1126/science.1141634. View

12.

Matimba A, Li F, Livshits A, Cartwright C, Scully S, Fridley B . Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes. Pharmacogenomics. 2014; 15(4):433-47. PMC: 4027966. DOI: 10.2217/pgs.13.226. View

13.

Lennard L, Welch J, Lilleyman J . Mercaptopurine in childhood leukaemia: the effects of dose escalation on thioguanine nucleotide metabolites. Br J Clin Pharmacol. 1996; 42(4):525-7. PMC: 2042700. DOI: 10.1046/j.1365-2125.1996.44921.x. View

14.

Schmiegelow K, Bjork O, Glomstein A, Gustafsson G, Keiding N, Kristinsson J . Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol. 2003; 21(7):1332-9. DOI: 10.1200/JCO.2003.04.039. View

15.

Kadan-Lottick N, Ness K, Bhatia S, Gurney J . Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia. JAMA. 2003; 290(15):2008-14. DOI: 10.1001/jama.290.15.2008. View

16.

Fessing M, Krynetski E, Zambetti G, Evans W . Functional characterization of the human thiopurine S-methyltransferase (TPMT) gene promoter. Eur J Biochem. 1998; 256(3):510-7. DOI: 10.1046/j.1432-1327.1998.2560510.x. View

17.

Caliskan M, Cusanovich D, Ober C, Gilad Y . The effects of EBV transformation on gene expression levels and methylation profiles. Hum Mol Genet. 2011; 20(8):1643-52. PMC: 3063990. DOI: 10.1093/hmg/ddr041. View

18.

Ameyaw M, Powrie R, Ofori-Adjei D, McLeod H . Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet. 1999; 8(2):367-70. DOI: 10.1093/hmg/8.2.367. View

19.

McLeod H, Krynetski E, Relling M, Evans W . Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia. 2000; 14(4):567-72. DOI: 10.1038/sj.leu.2401723. View

20.

Willer C, Li Y, Abecasis G . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010; 26(17):2190-1. PMC: 2922887. DOI: 10.1093/bioinformatics/btq340. View