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 55 different population samples, respectively. Furthermore, we showed how demographic history can affect pharmacogenetic variation at a micro-geographic scale by analysing 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 twelve CYP2D6 variable sites affecting enzymatic activity. Results and 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 3 pharmacogenetic loci; and (iv) several geographic regions of pharmacogenetic interest are still poorly characterized.
Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and micro-geographic scales
FUSELLI, Silvia;
2009
Abstract
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 55 different population samples, respectively. Furthermore, we showed how demographic history can affect pharmacogenetic variation at a micro-geographic scale by analysing 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 twelve CYP2D6 variable sites affecting enzymatic activity. Results and 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 3 pharmacogenetic loci; and (iv) several geographic regions of pharmacogenetic interest are still poorly characterized.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
