title: Warfarin pharmacogenetics: development of a dosing algorithm for Omani patients.
abstract: The objective of our present study was to develop a warfarin dosing algorithm for the Omani patients, as performances of warfarin dosing algorithms vary across populations with impact on the daily maintenance dose. We studied the functional polymorphisms of CYP2C9, CYP4F2 and VKORC1 genes to evaluate their impact on the warfarin maintenance dose in an admixed Omani patient cohort with Caucasian, African and Asian ancestries. We observed a 64-fold inter-patient variability for warfarin to achieve stable international normalized ratio in these patients. Univariate analysis revealed that age, gender, weight, atrial fibrillation, deep vein thrombosis/pulmonary embolism and variant genotypes of CYP2C9 and VKORC1 loci were significantly associated with warfarin dose in the studied patient population. However, multiple regression model showed that only the atrial fibrillation, and homozygous CYP2C9 variant genotypes (*2/*3 and *3/*3) and VKORC1 GA and AA genotypes remained significant. A multivariate model, which included demographic, clinical and pharmacogenetic variables together explained 63% of the overall inter-patient variability in warfarin dose requirement in this microgeographically defined, ethnically admixed Omani patient cohort on warfarin. This locally developed model performed much better than the International Warfarin Pharmacogenetics Consortium (IWPC) model as the latter could only explain 34% of the inter-patient variability in Omani patients. VKORC1 3673G>A polymorphism emerged as the single most important predictor of warfarin dose variability, even in this admixed population (partial R(2)=0.45).
authors.affiliation: Department of Haematology, Sultan Qaboos University Hospital, Muscat, Oman. pathare@squ.edu.om
authors.forename: Anil
authors.initials: A
authors.lastname: Pathare
authors.forename: Murtadha
authors.initials: M
authors.lastname: Al Khabori
authors.forename: Salam
authors.initials: S
authors.lastname: Alkindi
authors.forename: Shoaib
authors.initials: S
authors.lastname: Al Zadjali
authors.forename: Rhea
authors.initials: R
authors.lastname: Misquith
authors.forename: Hammad
authors.initials: H
authors.lastname: Khan
authors.forename: Claudine
authors.initials: C
authors.lastname: Lapoumeroulie
authors.forename: Andras
authors.initials: A
authors.lastname: Paldi
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Krishnamoorthy
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001281:Atrial Fibrillation / Q000188:drug therapy; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D054796:Drug Dosage Calculations; D005006:Ethnicity / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D005828:Genetics, Population / Q000379:methods; D005838:Genotype; D006801:Humans; D016014:Linear Models; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D009850:Oman / Q000208:ethnology; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D020246:Venous Thrombosis / Q000188:drug therapy; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; 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