170 Original article Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales Johanna Sistonen a , Silvia Fuselli b , Jukka U. Palo a , Neelam Chauhan c , Harish Padh c and Antti Sajantila a Objectives 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. Results and conclusion 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. Pharmacogenetics and Genomics 19:170–179  c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. Pharmacogenetics and Genomics 2009, 19:170–179 Keywords: CYP2C9, CYP2C19, CYP2D6, genetic variation, human populations, polymorphism a Department of Forensic Medicine, University of Helsinki, Helsinki, Finland, b Department of Biology and Evolution, University of Ferrara, Ferrara, Italy and c B.V. Patel Pharmaceutical Education and Research Development Centre, Thaltej, Ahmedabad, India Correspondence to Johanna Sistonen, MSc, or Antti Sajantila, MD, PhD, Department of Forensic Medicine, PO Box 40, 00014 University of Helsinki, Helsinki, Finland Tel: + 358 9 1911; fax: + 358 9 1912 7518; e-mail: johanna.sistonen@helsinki.fi; antti.sajantila@helsinki.fi Received 23 April 2008 Accepted 21 October 2008 Introduction Cytochrome P450 (CYP) enzymes are responsible for the metabolism of both endogenous and exogenous compounds in the human body. Among the 18 identified human CYP families, CYP2 is the most diverse, associated primarily with phase I metabolism of a large number of foreign compounds [1]. The CYP2 family includes a variety of drug-metabolizing enzymes (DMEs) coded by polymorphic genes (http://www.cypalleles.ki.se/). Within this gene family molecular variation at loci coding for CYP2C9, CYP2C19, and CYP2D6 has the most important clinical consequences [2]. CYP2D6 (OMIM 124030), located at 22q13.1 in the CYP2D cluster [3,4], is one of the best characterized genes coding for DMEs. It is highly polymorphic with more than 60 major genetic variants described to date, and the phenotypic consequences of this variation are considerable. The CYP2D6 enzyme activity ranges from complete deficiency to ultrarapid metabolism. CYP2C9 (OMIM 601130) and CYP2C19 (OMIM 124020), which are part of CYP2C gene cluster on chromosome 10q24 [5], also exhibit common genetic polymorphisms associated with altered activity of the corresponding enzymes. Regional differences in the frequency of CYP genetic variants leading to population-specific DME activity patterns are observed. In a recent study, we described the CYP2D6 molecular diversity on a global scale [6], whereas no similar studies on CYP2C9 and CYP2C19 are available to date. In this study, we genotyped new population samples and performed a systematic collection of CYP2C9, CYP2C19, and CYP2D6 data from the literature. In addition to being a resource for variant frequencies in specific populations of interest, these data allow comparison of pharmaco- genetic variation between populations and geographic regions and highlight which areas of the world still need to be characterized. The Finnish population is considered a genetic isolate with variation at the genome level strongly affected by 1744-6872  c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FPC.0b013e32831ebb30 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.