DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Thiopurine methyltransferase activity in acute lymphoblastic leukemia patients treated with mercaptopurines. The EFO term thiopurine methyltransferase activity measurement, response to mercaptopurine, acute lymphoblastic leukemia was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: thiopurine methyltransferase activity measurement, response to mercaptopurine, acute lymphoblastic leukemia

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

C Liu, W Yang, D Pei, C Cheng, C Smith, W Landier, L Hageman, Y Chen, JJ Yang, KR Crews, N Kornegay, SE Karol, FL Wong, S Jeha, JT Sandlund, RC Ribeiro, JE Rubnitz, ML Metzger, CH Pui, WE Evans, S Bhatia, MV Relling

TITLE:

Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait.

JOURNAL:

Clinical pharmacology and therapeutics Mar 2017, Vol 101, pp. 373-381

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. PUBMED: 27564568
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