title: Genome-wide association analysis identified splicing single nucleotide polymorphism in CFLAR predictive of triptolide chemo-sensitivity.
abstract: BACKGROUND
  Triptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f. Triptolide has been shown to induce apoptosis by activation of pro-apoptotic proteins, inhibiting NFkB and c-KIT pathways, suppressing the Jak2 transcription, activating MAPK8/JNK signaling and modulating the heat shock responses.
  
  
  RESULTS
  In the present study, we used lymphoblast cell lines (LCLs) derived from 55 unrelated Caucasian subjects to identify genetic markers predictive of cellular sensitivity to triptolide using genome wide association study. Our results identified SNPs on chromosome 2 associated with triptolide IC50 (p < 0.0001). This region included biologically interesting genes as CFLAR, PPIl3, Caspase 8/10, NFkB and STAT6. Identification of a splicing-SNP rs10190751, which regulates CFLAR alternatively spliced isoforms predictive of the triptolide cytotoxicity suggests its role in triptolides action. Our results from functional studies in Panc-1 cell lines further demonstrate potential role of CFLAR in triptolide toxicity. Analysis of gene-expression with cytotoxicity identified JAK1 expression to be a significant predictor of triptolide sensitivity.
  
  
  CONCLUSIONS
  Overall out results identified genetic factors associated with triptolide chemo-sensitivity thereby opening up opportunities to better understand its mechanism of action as well as utilize these biomarkers to predict therapeutic response in patients.
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA. lchauhan@cop.ufl.edu.
authors.forename: Lata
authors.initials: L
authors.lastname: Chauhan
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. Jenkins.Gregory@mayo.edu.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Jenkins
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA. bhise002@umn.edu.
authors.forename: Neha
authors.initials: N
authors.lastname: Bhise
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA. feldb001@umn.edu.
authors.forename: Tanya
authors.initials: T
authors.lastname: Feldberg
authors.affiliation: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA. tmitragh@umn.edu.
authors.forename: Taraswi
authors.initials: T
authors.lastname: Mitra-Ghosh
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA. bfridley@kumc.edu.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA. jlamba@cop.ufl.edu.
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
mesh_terms: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000633:toxicity; D004365:Drugs, Chinese Herbal; D004852:Epoxy Compounds / Q000737:chemistry / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D010616:Phenanthrenes / Q000737:chemistry / Q000633:toxicity; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D034622:RNA Interference; D012326:RNA Splicing; D034741:RNA, Small Interfering / Q000378:metabolism; D029757:Tripterygium / Q000737:chemistry / Q000378:metabolism
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D004224:Diterpenes; D004365:Drugs, Chinese Herbal; D004852:Epoxy Compounds; D010616:Phenanthrenes; D034741:RNA, Small Interfering; C001899:triptolide; C507904:JAK1 protein, human; D053613:Janus Kinase 1