Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians

Abstract

The polymorphic cytochrome P450 2D6 (CYP2D6) causing poor, extensive or ultrarapid metabolism of several clinically important drugs exhibits pronounced interethnic variation. Ultrarapid metabolism is caused by multiple copies of active CYP2D6 genes and recently 29% of an Ethiopian population has been shown to carry duplicated or multiduplicated CYP2D6 genes, whereas the corresponding frequency in other black, Oriental and European populations investigated is 1-2%. In order to characterize the distribution of alleles with multiple CYP2D6 copies in a neighbouring population and to characterize the CYP2D locus in general among Saudi Arabians, the CYP2D6 genotype of a Saudi Arabian population was examined using restriction fragment length polymorphism (RFLP) analysis and allele-specific polymerase chain reaction (PCR) amplification. Of 101 Saudi Arabians studied, 21 subjects had an EcoRI fragment indicative of CYP2D6 gene duplication. In contrast, only two individuals were heterozygous for a deletion of the whole gene (CYP2D6*5). The allele frequency of CYP2D6*4, the most common defective allele among Caucasians, was only 3.5% in the Saudi population. Two other alleles, CYP2D6*10 and *17, common in certain populations and which cause diminished enzyme activity, were found only at low allele frequencies of 3.0% each. These findings are in agreement with earlier Saudi Arabian phenotyping studies which reported a low frequency (1-2%) of poor metabolizers for CYP2D6 probe drugs. In conclusion, the Saudi Arabian population studied exhibited very few defective alleles and a large number of subjects carried duplicated CYP2D6 genes, implying a high conservation on functional CYP2D6 genes possibly due to dietary reasons and reveal the Saudi Arabians as an unique population in comparison with others examined.