title: Warfarin anticoagulant therapy: a Southern Italy pharmacogenetics-based dosing model.
abstract: OBJECTIVE
  Warfarin is the most frequently prescribed anticoagulant worldwide. However, warfarin therapy is associated with a high risk of bleeding and thromboembolic events because of a large interindividual dose-response variability. We investigated the effect of genetic and non genetic factors on warfarin dosage in a South Italian population in the attempt to setup an algorithm easily applicable in the clinical practice.
  
  
  METHODS
  A total of 266 patients from Southern Italy affected by cardiovascular diseases were enrolled and their clinical and anamnestic data recorded. All patients were genotyped for CYP2C9 2, 3, CYP4F2 3, VKORC1 -1639 G>A by the TaqMan assay and for variants VKORC1 1173 C>T and VKORC1 3730 G>A by denaturing high performance liquid chromatography and direct sequencing. The effect of genetic and not genetic factors on warfarin dose variability was tested by multiple linear regression analysis, and an algorithm based on our data was established and then validated by the Jackknife procedure.
  
  
  RESULTS
  Warfarin dose variability was influenced, in decreasing order, by VKORC1-1639 G>A (29.7%), CYP2C9 3 (11.8%), age (8.5%), CYP2C9 2 (3.5%), gender (2.0%) and lastly CYP4F2 3 (1.7%); VKORC1 1173 C>T and VKORC1 3730 G>A exerted a slight effect (<1% each). Taken together, these factors accounted for 58.4% of the warfarin dose variability in our population. Data obtained with our algorithm significantly correlated with those predicted by the two online algorithms: Warfarin dosing and Pharmgkb (p<0.001; R(2) = 0.805 and p<0.001; R(2) = 0.773, respectively).
  
  
  CONCLUSIONS
  Our algorithm, which is based on six polymorphisms, age and gender, is user-friendly and its application in clinical practice could improve the personalized management of patients undergoing warfarin therapy.
authors.affiliation: CEINGE- Biotecnologie Avanzate s.c.ar.l., Napoli, Italy ; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mazzaccara
authors.forename: Valeria
authors.initials: V
authors.lastname: Conti
authors.forename: Rosario
authors.initials: R
authors.lastname: Liguori
authors.forename: Vittorio
authors.initials: V
authors.lastname: Simeon
authors.forename: Mario
authors.initials: M
authors.lastname: Toriello
authors.forename: Angelo
authors.initials: A
authors.lastname: Severini
authors.forename: Corrado
authors.initials: C
authors.lastname: Perricone
authors.forename: Alfonso
authors.initials: A
authors.lastname: Meccariello
authors.forename: Pasquale
authors.initials: P
authors.lastname: Meccariello
authors.forename: Dino Franco
authors.initials: DF
authors.lastname: Vitale
authors.forename: Amelia
authors.initials: A
authors.lastname: Filippelli
authors.forename: Lucia
authors.initials: L
authors.lastname: Sacchetti
mesh_terms: D000368:Aged; D000465:Algorithms; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D007558:Italy; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D016133:Polymerase Chain Reaction; D012044:Regression Analysis; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases