Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait

Abstract

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 251 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.

Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update

“…Three TPMT single nucleotide polymorphisms (SNPs), which result in unstable proteins and enhanced TPMT protein degradation, account for over 90% of low activity phenotypes and are the most common inactivating alleles, and so genotyping tests including these three variants have a high likelihood of being informative for TPMT phenotype . Complementary phenotype laboratory tests can be helpful adjuncts to genotyping tests ( Supplement , Other Considerations) …”

“…Some of the clinical data upon which dosing recommendations are based ( Table 2 ) rely on measures of TPMT phenotype rather than genotype; however, because TPMT genotype is strongly linked to TPMT phenotype, these recommendations apply regardless of the method used to assess TPMT status.…”

Personalized medicine: Genetic risk prediction of drug response

“…Of interest, a recent GWAS of > 1000 children with leukemia found TPMT as the only gene achieving genome-wide significance –– top hit was rs1142345; 719A > G; P = 8.6 × 10 −61 (Liu et al, 2016), thereby supporting the idea that differences in TPMT activity might reflect a Mendelian, or predominantly oligogenic, trait. These data further confirm the clinical usefulness of the red-cell TPMT enzyme assay, which is a phenotype (not genotype) test, because discovery of a completely new DNA variant that causes low TPMT enzyme activity is always possible.…”

Bringing a genomic perspective to the safety of drug treatment in oncology

“…Genotyping of patient germline DNA can be obtained before therapy, to assess whether such genetic predisposition exists 13 . Most genetic biomarkers of drug safety have been identified after evidence has been achieved on various domains 14– 16 . These domains include the elucidation of the pharmacological properties of the drug, knowledge of the main disposition pathways linking drug exposure to the occurrence of the adverse effects, obtaining functional validation of the genetic marker in vitro , establishing the analytical validity of the genotyping assay, and demonstration of clinical validity and utility 17 .…”