Polymorphic variation in : A meta‐analysis of three genome‐wide association studiesTPMT: A meta‐analysis of three genome‐wide association studies is the principal determinant of TPMT phenotype: A meta‐analysis of three genome‐wide association studies

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Mercaptopurine (MP) is important for maintenance therapy of childhood acute lymphoblastic leukemia (ALL).1 The S‐methylation of MP is catalyzed by the cytosolic enzyme thiopurine S‐methyltransferase (TPMT). Over 30 polymorphisms in TPMT have been documented that have an effect on the enzymatic activity of TPMT.2 The most common alleles seen in most ethnicities are TPMT*3C (719A>G) and TPMT*3A (460G>A and 719A>G). There is a body of evidence that functional polymorphisms in TPMT are a determinant of MP‐related hematotoxicity,5 with myelosuppression seen in patients with TPMT deficiency receiving standard MP therapy.6 Furthermore, intermediate TPMT activity, only partly explained by TPMT heterozygosity present in 10% of individuals,8 is also associated with an increased risk of toxicity.5 Recently, a prospective clinical trial confirmed a lower incidence of leukopenia in pretreatment TPMT heterozygous‐tested patients with inflammatory bowel disease (IBD) after dose‐adjusted thiopurine therapy.9
While TPMT genotyping is advocated clinically by international guidelines using dosage individualization to limit MP‐related toxicity,5 TPMT activity shows considerable variability even in those with low‐risk TPMT genotypes, presumably as a consequence of as yet unidentified additional genetic or nongenetic factors.11 Although several studies have been performed trying to identify additional factors apart from the TPMT gene that influence TPMT activity,12 thus far the genome‐wide association study (GWAS) approach has not been used to comprehensively investigate the relationship between constitutional genotype and TPMT activity in red blood cells (RBCs). Moreover, systematic data regarding the correlation between TPMT genotype and TPMT expression or function in human liver, as the predominant site of thiopurine metabolism, is still missing.
To address this deficiency we have conducted the so‐far largest meta‐analysis of three independent GWAS of TPMT activity, comprising 844 individuals of the Estonian population cohort and 245 pediatric ALL cases, as well as 123 human livers.
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