title: Thiopurine pharmacogenomics: association of SNPs with clinical response and functional validation of candidate genes.
abstract: OBJECTIVE
  We investigated candidate genes associated with thiopurine metabolism and clinical response in childhood acute lymphoblastic leukemia.
  
  
  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.
  
  
  CONCLUSIONS
  The clinical response to thiopurines may be regulated by variation in known thiopurine pathway genes and additional novel genes outside of the thiopurine pathway.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Matimba
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Alina
authors.initials: A
authors.lastname: Livshits
authors.forename: Cher S
authors.initials: CS
authors.lastname: Cartwright
authors.forename: Stephen
authors.initials: S
authors.lastname: Scully
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Gregory
authors.initials: G
authors.lastname: Jenkins
authors.forename: Anthony
authors.initials: A
authors.lastname: Batzler
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Weinshilboum
authors.forename: Lynne
authors.initials: L
authors.lastname: Lennard
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D013866:Thioguanine / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D015122:Mercaptopurine; D013866:Thioguanine