title: Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy.
abstract: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding.
  
  
  
  In total, 982 warfarin-treated patients from the RE-LY trial were studied.
  
  
  
  After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R(2) by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding.
  
  
  
  We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.
authors.affiliation: Uppsala Clinical Research Center & Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Niclas
authors.initials: N
authors.lastname: Eriksson
authors.affiliation: Uppsala Clinical Research Center & Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Uppsala Clinical Research Center & Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Berglund
authors.affiliation: Department Medical Sciences & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Axelsson
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences & McMaster University, Hamilton, ON, Canada.
authors.forename: Stuart
authors.initials: S
authors.lastname: Connolly
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences & McMaster University, Hamilton, ON, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Eikelboom
authors.affiliation: Sidney Kimmel Medical Collage at Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ezekowitz
authors.affiliation: Uppsala Clinical Research Center & Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Oldgren
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences & McMaster University, Hamilton, ON, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
authors.affiliation: Boehringer Ingelheim Pharma Inc, Ridgefield, CT, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Reilly
authors.affiliation: Department Medical Sciences & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: Department Medical Sciences & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvanen
authors.affiliation: Department of Immunology, Genetics & Pathology & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Wadelius
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences & McMaster University, Hamilton, ON, Canada.
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.affiliation: Department Medical Sciences & Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Wadelius
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D000072470:Cytochrome P450 Family 4 / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D023281:Genomics; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: CYP2C9; CYP4F2; VKORC1; genome-wide association study; prediction models; time in therapeutic range; warfarin; warfarin dose