Genetic and clinical factors relating to warfarin dosing.
Warfarin has a narrow therapeutic window and the hemorrhagic or thrombotic implications of over- or under-dosing can be devastating. Moreover, there is substantial individual variation in response to warfarin. This review describes the genetic and clinical factors associated with warfarin dosing, including recent developments. The pivotal role of CYP2C9 and VKORC1 is emphasized because polymorphisms of these two genes account for approximately 40% of the variation in dose requirements. Recent studies have reported that polymorphisms in CYP4F2 might account for between 2 and 7% of the variation. Large studies published recently, including the Warfarin Genetics (WARG) study and the International Warfarin Pharmacogenetic Consortium, have added to our understanding of factors relating to warfarin dosing. Several prospective studies have evaluated genotype-guided dosing, but these have found negative results or were poorly designed. Whether genotype-guided dosing is clinically beneficial remains unclear, but studies are currently underway that will help to determine this.
Jonas
Daniel E
DE
University of North Carolina, Chapel Hill, 5039 Old Clinic Building, Campus Box 7110, Chapel Hill, NC 27599, USA.
McLeod
Howard L
HL
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D018849:Controlled Clinical Trials as Topic / Q000379:methods; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods; D006899:Mixed Function Oxygenases / Q000235:genetics; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases