title: Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales.
abstract: OBJECTIVE
  CYP2C9, CYP2C19, and CYP2D6 belong to a subfamily of cytochrome P450 (CYP) enzymes, associated mainly with the metabolism of exogenous compounds in the human body. The genes coding for these enzymes are highly polymorphic and thus of major pharmacogenetic importance. By systematically retrieving data from the literature and genotyping new population samples, we aimed at describing the worldwide distribution of genetic variation at these loci. We created a comprehensive resource of frequency data for the most important CYP2C9, CYP2C19, and CYP2D6 genetic variants in 129, 146, and 138 different population samples, respectively. Furthermore, we showed how demographic history can affect pharmacogenetic variation at a microgeographic scale by analyzing regional samples from Finland, which represents a well-known genetic isolate.
  
  
  METHODS
  Data were obtained from the literature from 1991 to 2007 as well as by genotyping new population samples at four CYP2C9, two CYP2C19, and 12 CYP2D6 variable sites affecting enzymatic activity.
  
  
  CONCLUSIONS
  Our study shows that: (i) altered activity variants of CYP2C9, CYP2C19, and CYP2D6 occur globally in all geographic regions, reaching extremely high frequencies in some populations; (ii) each of the CYP genes studied shows a distinct geographic pattern of variation; (iii) population substructure can strongly affect the variation seen in pharmacogenetic loci; and (iv) several geographic regions of pharmacogenetic interest are still poorly characterized.
authors.affiliation: Department of Forensic Medicine, University of Helsinki, Helsinki, Finland. johanna.sistonen@helsinki.fi
authors.forename: Johanna
authors.initials: J
authors.lastname: Sistonen
authors.forename: Silvia
authors.initials: S
authors.lastname: Fuselli
authors.forename: Jukka U
authors.initials: JU
authors.lastname: Palo
authors.forename: Neelam
authors.initials: N
authors.lastname: Chauhan
authors.forename: Harish
authors.initials: H
authors.lastname: Padh
authors.forename: Antti
authors.initials: A
authors.lastname: Sajantila
mesh_terms: D000349:Africa; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D019143:Evolution, Molecular; D005387:Finland; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D005843:Geography; D006801:Humans; D007194:India; D011110:Polymorphism, Genetic; D011156:Population Density
chemical_list: C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6