TY - JOUR
T1 - Warfarin pharmacogenetics
T2 - Development of a dosing algorithm for Omani patients
AU - Pathare, Anil
AU - Al Khabori, Murtadha
AU - Alkindi, Salam
AU - Al Zadjali, Shoaib
AU - Misquith, Rhea
AU - Khan, Hammad
AU - Lapoumeroulie, Claudine
AU - Paldi, Andras
AU - Krishnamoorthy, Rajagopal
PY - 2012/10
Y1 - 2012/10
N2 - 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).
AB - 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).
KW - CYP2C9
KW - CYP4F2
KW - VKORC1
KW - Warfarin
KW - admixture
KW - resistance
KW - sensitive
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UR - http://www.scopus.com/inward/citedby.url?scp=84867923548&partnerID=8YFLogxK
U2 - 10.1038/jhg.2012.94
DO - 10.1038/jhg.2012.94
M3 - Article
C2 - 22854539
AN - SCOPUS:84867923548
SN - 1434-5161
VL - 57
SP - 665
EP - 669
JO - Journal of Human Genetics
JF - Journal of Human Genetics
IS - 10
ER -