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 Forensic Medicine, University of Helsinki, 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.
    Annals of Human Biology 09/2015; DOI:10.3109/03014460.2015.1068372 · 1.27 Impact Factor
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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.
    SpringerPlus 12/2013; 2(1):52. DOI:10.1186/2193-1801-2-52
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    • "For example, the prevalence of PMs is estimated to be 5 – 10% in Caucasian populations and only 1 – 2% in Asian populations, whereas UMs constitute only 1 – 2% in Caucasian populations, but up to 30 – 40% in some Northern African populations (Sistonen et al., 2007 "
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    ABSTRACT: Abstract Genetic testing may help to improve treatment outcomes in order to avoid non-response or severe side effects to psychotropic medication. Most robust data have been obtained for gene variants in CYP2D6 and CYP2C19 enzymes for antipsychotics and antidepressant treatment. We reviewed original articles indexed in PubMed from 2008-2013 on CYP2D6 and CYP2C19 gene variants and treatment outcome to antidepressant or antipsychotic medication. We have started providing CYP2D6 and CYP2C19 genotype information to physicians and conducted a survey where preliminary results are reported. Studies provided mixed results regarding the impact of CYP2D6 and CYP2C19 gene variation on treatment response. Plasma levels were mostly found associated with CYP metabolizer status. Higher occurrence/severity of side effects were reported in non-extensive CYP2D6 or CYP2C19 metabolizers. Results showed that providing genotypic information is feasible and generally well accepted by both patients and physicians. Although currently available studies are limited by small sample sizes and infrequent plasma drug level assessment, research to date indicates that CYP2D6 and CYP2C19 testing may be beneficial particularly for non-extensive metabolizing patients. In summary, clinical assessment of CYP2D6 and CYP2C19 metabolizer status is feasible, well accepted and optimizes drug treatment in psychiatry.
    International Review of Psychiatry 10/2013; 25(5):554-71. DOI:10.3109/09540261.2013.838944 · 1.80 Impact Factor
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