Sistonen J, Sajantila A, Lao O, et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure

Department of Mathematics and Statistics, University of Helsinki, Helsinki, Uusimaa, Finland
Pharmacogenetics and Genomics (Impact Factor: 3.48). 03/2007; 17(2):93-101. DOI: 10.1097/01.fpc.0000239974.69464.f2
Source: PubMed


CYP2D6, a member of the cytochrome P450 superfamily, is responsible for the metabolism of about 25% of the commonly prescribed drugs. Its activity ranges from complete deficiency to excessive activity, potentially causing toxicity of medication or therapeutic failure with recommended drug dosages. This study aimed to describe the CYP2D6 diversity at the global level.
A total of 1060 individuals belonging to 52 worldwide-distributed populations were genotyped at 12 highly informative variable sites, as well as for gene deletion and duplications. Phenotypes were predicted on the basis of haplotype combinations.
Our study shows that (i) CYP2D6 diversity is far greater within than between populations and groups thereof, (ii) null or low-activity variants occur at high frequencies in various areas of the world, (iii) linkage disequilibrium is lowest in Africa and highest in the Americas. Patterns of variation, within and among populations, are similar to those observed for other autosomal markers (e.g. microsatellites and protein polymorphisms), suggesting that the diversity observed at the CYP2D6 locus reflects the same factors affecting variation at random genome markers.

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    • "Polymorphisms in the CYP2C9 gene modulate interindividual heterogeneity in the body's response to various endogenous and exogenous substrates. The diversity of CYP2C9 alleles varies considerably across geographic locations and ethnic groups (Sistonen et al., 2007). Nevertheless, to date, the distribution of CYP2C9 polymorphisms has only been studied in a few archaic populations such as Bolivians (Bravo-Villalta et al., 2005), Maori (Lea et al., 2008) and Ghanaians (Kudzi et al., 2009). "
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    ABSTRACT: Background: CYP2C9 gene polymorphisms modulate inter-individual variations in the human body's responses to various endogenous and exogenous drug substrates. To date, little is known about the CYP2C9 gene polymorphisms among the aboriginal populations of the world, including those in Malaysia. Aim: To characterise and compare the CYP2C9 polymorphisms (CYP2C9*2, CYP2C9*3, CYP2C9*4 and CYP2C9*5) between one of Malaysia's aboriginal populations, Jahai, with the national major ethnic, Malay. To also compare the allele frequencies from these two populations with available data of other aboriginal populations around the world. Subjects and methods: The extracted DNA of 155 Jahais and 183 Malays was genotyped for CYP2C9 polymorphisms using a nested multiplex allele-specific polymerase chain reaction technique. The results were confirmed by DNA direct sequencing. Results: Genotyping results revealed that CYP2C9*2, CYP2C9*4 and CYP2C9*5 were absent in Jahais, while only the latter two were absent in Malays. The CYP2C9*3 allelic frequency in Jahais was 36.2%, making them the most frequent carriers of the allele thus far reported in any ethnic group from Southeast Asia. Conclusions: The high frequency of CYP2C9*3 and the absence of CYP2C9*2 in Jahais suggest that genetic drift may be occurring in this ethnic group. This is the first study to determine the CYP2C9 polymorphisms in an aboriginal population in Malaysia.
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    • "CYP2D6 is a highly polymorphic gene with more than 70 different allelic variants. We chose these star alleles because they are more frequent in the Asian and Caucasian population (Bradford 2002; Sistonen et al. 2007; Veiga et al. 2009). Tamoxifen and its metabolites were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) as described elsewhere (Irvin et al. 2011). "
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    ABSTRACT: While tamoxifen activity is mainly due to endoxifen and the concentration of this active metabolite is, in part, controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results. In an exploratory study, we determined the CYP2D6 metabolic status and plasma concentrations of endoxifen among 224 Filipino and Vietnamese women participating in a clinical trial of adjuvant hormonal therapy for operable breast cancer. We further conducted a nested-case-control study among 48 women (half with recurrent disease, half without) investigating the relationship of endoxifen concentrations and recurrence of disease. We found a significant association of reduced endoxifen plasma concentrations with functionally important CYP2D6 genotypes. High endoxifen concentrations were associated with higher risk of recurrence; with a quadratic trend fitted to a stratified Cox proportional hazards regression model, the likelihood ratio p-value was 0.002. The trend also showed that in 8 out of 9 pairs with low endoxifen concentrations, the recurrent case had lower endoxifen levels than the matched control. This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy. In particular, at higher concentrations (>70, endoxifen may promote recurrence.
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    • "For brevity, this paragraph highlights ethnic diversity using a few selected allelic variants as examples as their frequencies among ethnicities and populations can vary dramatically. The frequency of the non-functional CYP2D6 * 4 allele for instance can be extremely low or even absent in some east Asian and Oceanian populations (Lee et al., 2009;Myrand et al., 2008;Qin et al., 2008;Sistonen et al., 2007;von Ahsen et al., 2010) while frequencies in Europeans range between 15 – 20%, but can be over 30% as reported for the Faroese (Halling et al., 2005). In contrast, Asians exhibit a marked shift towards overall slower CYP2D6 activity on a population basis when comparing urinary metabolic ratios (Johansson et al., 1994;Kitada, 2003;Tateishi et al., 1999), which can be explained by high frequencies of up to 64% (averaging about 42%) of the CYP2D6 * 10 reduced function allele. "
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    ABSTRACT: Abstract Cytochrome P450 2D6 (CYP2D6) plays an important role in the metabolism and bioactivation of about 25% of clinically used drugs including many antidepressants, antipsychotics and opioids. CYP2D6 activity is highly variably ranging from no activity in so-called poor metabolizers to ultrarapid metabolism at the other end of the extreme of the activity distribution. A large portion of this variability can be explained by the highly polymorphic nature of the CYP2D6 gene locus for which > 100 variants and subvariants identified to date. Allele frequencies vary markedly between ethnic groups; some have exclusively or predominantly only been observed in certain populations. Pharmacogenetic testing holds the promise of individualizing drug therapy by identifying patients with CYP2D6 diplotypes that puts them at an increased risk of experiencing dose-related adverse events or therapeutic failure. Inferring a patient's CYP2D6 metabolic capacity, or phenotype, however, is a challenging task due to the complexity of the CYP2D6 gene locus. Allelic variation includes SNPs, small insertions and deletions, gene copy number variation and rearrangements with CYP2D7, a highly related non-functional gene. This review provides a summary of the intricacies of CYP2D6 variation and genotype analysis, knowledge that is invaluable for the translation of genotype into clinically useful information.
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