title: Novel regulatory variant detected on the VKORC1 haplotype that is associated with warfarin dose.
abstract: Warfarin dose requirement is associated with VKORC1 rs9923231, and we studied whether it is a functional variant.
  
  
  
  We selected variants in linkage disequilibrium with rs9923231 that bind transcription factors in an allele-specific way. Representative haplotypes were cloned or constructed, nuclear protein binding and transcriptional activity were evaluated.
  
  
  
  rs56314408C>T and rs2032915C>T were detected in a liver enhancer in linkage disequilibrium with rs9923231. The rs56314408-rs2032915 C-C haplotype preferentially bound nuclear proteins and had higher transcriptional activity than T-T and the African-specific T-C. A motif for TFAP2A/C was disrupted by rs56314408T. No difference in transcriptional activity was detected for rs9923231G>A.
  
  
  
  Our results supported an activating role for rs56314408C, while rs9923231G>A had no evidence of being functional.
authors: Department of Immunology, Genetics & Pathology, & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Marco
authors: M
authors: Cavalli
authors: Department of Immunology, Genetics & Pathology, & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Gang
authors: G
authors: Pan
authors: Department of Immunology, Genetics & Pathology, & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Helena
authors: H
authors: Nord
authors: Uppsala Clinical Research Center & Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Niclas
authors: N
authors: Eriksson
authors: Department of Immunology, Genetics & Pathology, & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Claes
authors: C
authors: Wadelius
authors: Department of Medical Sciences & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Mia
authors: M
authors: Wadelius
mesh_terms: D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage* / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008099:Liver / Q000201:enzymology; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: regulatory sequences; vitamin K epoxide reductases; warfarin