Thiopurine pharmacogenomics: Association of SNPs with clinical response and functional validation of candidate genes

Alice Matimba; Fang Li; Alina Livshits; Cher S. Cartwright; Stephen Scully; Brooke L. Fridley; Gregory Jenkins; Anthony Batzler; Liewei Wang; Richard Weinshilboum; Lynne Lennard

doi:10.2217/pgs.13.226

Thiopurine pharmacogenomics: Association of SNPs with clinical response and functional validation of candidate genes

Alice Matimba, Fang Li, Alina Livshits, Cher S. Cartwright, Stephen Scully, Brooke L. Fridley, Gregory Jenkins, Anthony Batzler, Liewei Wang, Richard Weinshilboum, Lynne Lennard

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

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.

Original language	English (US)
Pages (from-to)	433-447
Number of pages	15
Journal	Pharmacogenomics
Volume	15
Issue number	4
DOIs	https://doi.org/10.2217/pgs.13.226
State	Published - Mar 2014
Externally published	Yes

Keywords

6-mercaptopurine
6-thioguanine
childhood acute lymphoblastic leukemia
single nucleotide polymorphisms
thiopurine pharmacogenomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.2217/pgs.13.226

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title = "Thiopurine pharmacogenomics: Association of SNPs with clinical response and functional validation of candidate genes",

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.",

keywords = "6-mercaptopurine, 6-thioguanine, childhood acute lymphoblastic leukemia, single nucleotide polymorphisms, thiopurine pharmacogenomics",

author = "Alice Matimba and Fang Li and Alina Livshits and Cartwright, {Cher S.} and Stephen Scully and Fridley, {Brooke L.} and Gregory Jenkins and Anthony Batzler and Liewei Wang and Richard Weinshilboum and Lynne Lennard",

year = "2014",

month = mar,

doi = "10.2217/pgs.13.226",

language = "English (US)",

volume = "15",

pages = "433--447",

journal = "Pharmacogenomics",

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T1 - Thiopurine pharmacogenomics

T2 - Association of SNPs with clinical response and functional validation of candidate genes

AU - Matimba, Alice

AU - Li, Fang

AU - Livshits, Alina

AU - Cartwright, Cher S.

AU - Scully, Stephen

AU - Fridley, Brooke L.

AU - Jenkins, Gregory

AU - Batzler, Anthony

AU - Wang, Liewei

AU - Weinshilboum, Richard

AU - Lennard, Lynne

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

KW - 6-mercaptopurine

KW - 6-thioguanine

KW - childhood acute lymphoblastic leukemia

KW - single nucleotide polymorphisms

KW - thiopurine pharmacogenomics

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Thiopurine pharmacogenomics: Association of SNPs with clinical response and functional validation of candidate genes

Abstract

Keywords

UN SDGs

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