title: Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements.
abstract: The aim of the study is to improve our understanding of the worldwide allele frequency distribution of four genetic polymorphisms known to influence warfarin dosing (VKORC1 rs9923231, CYP2C9 rs1799853, CYP2C9 rs1057910 and CYP4F2 rs2108622). These four polymorphisms were genotyped in the Human Genome Diversity Project-Centre Etude Polymorphism Humain (HGDP-CEPH) worldwide sample (N=963), as well as in a sample of individuals of European, East Asian and South Asian ancestry living in Canada (N=316). The VKORC1 rs9923231 single nucleotide polymorphism (SNP) showed an extensive geographic differentiation, with the derived T allele appearing at very high allele frequencies in East Asian populations. Results from several tests of positive selection indicate that this unusual distribution may be the result of positive selection in East Asia. Understanding the worldwide distribution of markers determining warfarin dosing is important for the future application of pharmacogenomic-based algorithms to different population groups.
authors.affiliation: Department of Anthropology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kendra A
authors.initials: KA
authors.lastname: Ross
authors.forename: Abbigail W
authors.initials: AW
authors.lastname: Bigham
authors.forename: Melissa
authors.initials: M
authors.lastname: Edwards
authors.forename: Agnes
authors.initials: A
authors.lastname: Gozdzik
authors.forename: Guilherme
authors.initials: G
authors.lastname: Suarez-Kurtz
authors.forename: Esteban J
authors.initials: EJ
authors.lastname: Parra
mesh_terms: D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D005006:Ethnicity; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
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