title: A multi-factorial analysis of response to warfarin in a UK prospective cohort.
abstract: BACKGROUND
  Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin.
  
  
  METHODS
  A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R.
  
  
  RESULTS
  VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role.
  
  
  CONCLUSIONS
  Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. s.bourgeois@qmul.ac.uk.
authors.forename: Stephane
authors.initials: S
authors.lastname: Bourgeois
authors.affiliation: University of Liverpool, Liverpool, Merseyside, L69 3GE, UK. A.L.Jorgensen@liverpool.ac.uk.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jorgensen
authors.affiliation: University of Liverpool, Liverpool, Merseyside, L69 3GE, UK. Eunice.Zhang@liverpool.ac.uk.
authors.forename: Eunice J
authors.initials: EJ
authors.lastname: Zhang
authors.affiliation: University of Liverpool, Liverpool, Merseyside, L69 3GE, UK. Anita.Hanson@liverpool.ac.uk.
authors.forename: Anita
authors.initials: A
authors.lastname: Hanson
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. mg@physics.org.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Gillman
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. sjb@sanger.ac.uk.
authors.forename: Suzannah
authors.initials: S
authors.lastname: Bumpstead
authors.affiliation: University of Liverpool, Liverpool, Merseyside, L69 3GE, UK. C.H.Toh@liverpool.ac.uk.
authors.forename: Cheng Hock
authors.initials: CH
authors.lastname: Toh
authors.affiliation: University of Liverpool, Liverpool, Merseyside, L69 3GE, UK. P.R.Williamson@liverpool.ac.uk.
authors.forename: Paula
authors.initials: P
authors.lastname: Williamson
authors.affiliation: Newcastle University, Newcastle upon Tyne, UK. a.k.daly@newcastle.ac.uk.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
authors.affiliation: Newcastle University, Newcastle upon Tyne, UK. farhad.kamali@newcastle.ac.uk.
authors.forename: Farhad
authors.initials: F
authors.lastname: Kamali
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. p.deloukas@qmul.ac.uk.|William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. p.deloukas@qmul.ac.uk.
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.affiliation: University of Liverpool, Liverpool, Merseyside, L69 3GE, UK. munirp@liverpool.ac.uk.|Royal Liverpool and Broadgreen University Hospital NHS Trust, Liverpool, L7 8XP, UK. munirp@liverpool.ac.uk.|The Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of Liverpool, Block A: Waterhouse Building, 1-5 Brownlow Street, Liverpool, L69 3GL, UK. munirp@liverpool.ac.uk.
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D006113:United Kingdom; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; 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