title: Building individualized medicine: prevention of adverse reactions to warfarin therapy.
abstract: Warfarin is the most widely used oral anticoagulant in the world for patients with venous thrombosis, pulmonary embolism, chronic atrial fibrillation, and prosthetic heart valves. Approximately 30 genes contribute to therapeutic effects of warfarin, and genetic polymorphisms in these genes may modulate its anticoagulant activity. In contrast to monogenic pharmacogenetic traits, warfarin drug response is a polygenic trait, and development of diagnostic tools predictive of adverse reactions to warfarin requires a novel approach. A combination of two strategies, biochemical isolation of allelic variants and linkage disequilibrium association studies, was used to find an association between genetic polymorphisms in the candidate genes and warfarin response. A strong association was found between genetic polymorphisms in six genes, including VKORC1, CYP2C9, PROC, EPHX1, GGCX, and ORM1, and interindividual variability in the anticoagulant effect of warfarin; the strongest predictors were VKORC1 and CYP2C9. Generation of single nucleotide polymorphism (SNP)-based dense genetic maps made it possible to identify haplotypes associated with drugresponse phenotypes. Discrimination between haplotypes associated with warfarin dose phenotypes can be achieved by a limited set of informative polymorphisms (tag SNPs). The use of tag SNPs in pharmacogenomic analysis provides a promising tool for dissecting polygenic traits of drug response.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, Pennsylvania 19140, USA. ekrynets@temple.edu
authors.forename: Evgeny
authors.initials: E
authors.lastname: Krynetskiy
authors.forename: Patrick
authors.initials: P
authors.lastname: McDonnell
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D004851:Epoxide Hydrolases / Q000235:genetics; D005838:Genotype; D006801:Humans; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009961:Orosomucoid / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011486:Protein C / Q000235:genetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D009961:Orosomucoid; D011486:Protein C; 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; D004851:Epoxide Hydrolases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase