Matimba, A., Li, F., Livshits, A. et al. (8 more authors) (2014) Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes. Pharmacogenomics, 15 (4). pp. 433-447. ISSN 1462-2416
Abstract
Aim: We investigated candidate genes associated with thiopurine metabolism and clinical response in childhood acute lymphoblastic leukemia. Materials & methods: We performed genome-wide SNP association studies of 6-thioguanine and 6-mercaptopurine cytotoxicity using lymphoblastoid cell lines. We then genotyped the top SNPs associated with lymphoblastoid cell line cytotoxicity, together with tagSNPs for genes in the ‘thiopurine pathway’ (686 total SNPs), in DNA from 589 Caucasian UK ALL97 patients. Functional validation studies were performed by siRNA knockdown in cancer cell lines. Results: SNPs in the thiopurine pathway genes ABCC4, ABCC5, IMPDH1, ITPA, SLC28A3 and XDH, and SNPs located within or near ATP6AP2, FRMD4B, GNG2, KCNMA1 and NME1, were associated with clinical response and measures of thiopurine metabolism. Functional validation showed shifts in cytotoxicity for these genes. Conclusion: The clinical response to thiopurines may be regulated by variation in known thiopurine pathway genes and additional novel genes outside of the thiopurine pathway.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2014 Future Medicine. This is an author produced version of a paper subsequently published in Pharmacogenomics. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | 6-mercaptopurine; 6-thioguanine; childhood acute lymphoblastic leukemia; single nucleotide polymorphisms; thiopurine pharmacogenomics |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Vice-Chancellor's Office (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 13 Feb 2017 09:56 |
Last Modified: | 24 Mar 2018 13:26 |
Published Version: | https://doi.org/10.2217/pgs.13.226 |
Status: | Published |
Publisher: | Future Medicine |
Refereed: | Yes |
Identification Number: | 10.2217/pgs.13.226 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:110819 |