Publications Repository

Publications Repository

View item 
  •   Home
  • ICR Divisions
  • Genetics and Epidemiology
  • View item
  • Home
  • ICR Divisions
  • Genetics and Epidemiology
  • View item
JavaScript is disabled for your browser. Some features of this site may not work without it.

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

Thumbnail
View/Open
Accepted version (1.658Mb)
Date
2017-05
ICR Author
Houlston, Richard
Author
Tamm, R
Mägi, R
Tremmel, R
Winter, S
Mihailov, E
Smid, A
Möricke, A
Klein, K
Schrappe, M
Stanulla, M
Houlston, R
Weinshilboum, R
Mlinarič Raščan, I
Metspalu, A
Milani, L
Schwab, M
Schaeffeler, E
Show allShow less
Type
Journal Article
Metadata
Show full item record
Abstract
Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 × 10<sup>-8</sup> ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 × 10<sup>-72</sup> ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage.
URI
https://repository.icr.ac.uk/handle/internal/4276
DOI
https://doi.org/10.1002/cpt.540
Collections
  • Genetics and Epidemiology
Subject
Humans
Methyltransferases
Phenotype
Polymorphism, Genetic
Alleles
Estonia
Genome-Wide Association Study
Research team
Cancer Genomics
Language
eng
Date accepted
2016-10-17
License start date
2017-05
Citation
Clinical pharmacology and therapeutics, 2017, 101 (5), pp. 684 - 695

Browse

All of ICR repositoryICR DivisionsBy issue dateAuthorsTitlesPublication TypesThis collectionBy issue dateAuthorsTitlesPublication Types
  • Login
  • Registered office: The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP
    A Charity, Not for Profit. Company Limited by Guarantee.
    Registered in England No. 534147. VAT Registration No. GB 849 0581 02.