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CYP2D6 worldwide genetic variation shows high frequency ofaltered activity variants and no continental structureJohanna Sistonena, Antti Sajantilaa, Oscar Laoc, Jukka Coranderb,Guido Barbujanid and Silvia Fusellia,d Background and objective CYP2D6, a member of the highest in the Americas. Patterns of variation, within cytochrome P450 superfamily, is responsible for the and among populations, are similar to those observed for metabolism of about 25% of the commonly prescribed other autosomal markers (e.g. microsatellites and protein drugs. Its activity ranges from complete deficiency to polymorphisms), suggesting that the diversity observed excessive activity, potentially causing toxicity of medication at the CYP2D6 locus reflects the same factors affecting or therapeutic failure with recommended drug dosages.
variation at random genome markers. Pharmacogenetics This study aimed to describe the CYP2D6 diversity at the Methods A total of 1060 individuals belonging to 52 Pharmacogenetics and Genomics 2007, 17:93–101 worldwide-distributed populations were genotyped at Keywords: CYP2D6, genetic variation, genotyping, polymorphism 12 highly informative variable sites, as well as for gene deletion and duplications. Phenotypes were predicted on Departments of aForensic Medicine, bMathematics and Statistics, University ofHelsinki, Finland, cDepartment of Forensic Molecular Biology, Erasmus University the basis of haplotype combinations.
Medical Center, DR Rotterdam, The Netherlands and dDepartment of Biology,University of Ferrara, Ferrara, Italy Results and conclusions Our study shows that (i) Correspondence and requests for reprints to Johanna Sistonen, Department of CYP2D6 diversity is far greater within than between Forensic Medicine, P.O. Box 40 00014 University of Helsinki, FinlandTel/fax: + 358 9 191 27450/27518; 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 Received 21 April 2006 Accepted 6 August 2006 function variants. These findings raise several questions Physiological responses to the same drug treatment are of evolutionary and applied relevance. First, such a high known to vary substantially between different indivi- diversity can hardly be maintained by a simple mechan- duals. In addition to external factors, these differences ism of directional selection common to all populations, or depend on variation at genes coding for proteins involved by genetic drift alone. As a consequence, more complex in the transportation of the drug to its site of action, its processes must be envisaged, and any explanation of the interaction with the target, and its metabolism. Among observed diversity must account for the local occurrence the genes coding for drug-metabolizing enzymes, CYP2D6 at substantial frequencies of null or reduced-activity (MIM 124030), a member of the cytochrome P450 variants. Second, CYP2D6 sequence diversity is clearly superfamily, is one of the best characterized. It is associated with phenotypic variation in the gene’s responsible for the metabolism of about 25% of commonly expression and activity, which in turn is part of a complex used drugs belonging to classes such as antidepressants, network of interactions of extreme pharmacogenetic and neuroleptics, b-blockers and antiarrhythmics [1]. The pharmacogenomic interest. A third question bears on the CYP2D6 gene is highly polymorphic with more than 50 interpretation of human diversity in general, which has recently been and still is the subject of intense debate cyp2d6.htm). The phenotypic consequences of this varia- (for reviews, see e.g. [3–8]). Some studies of neutral tion are considerable. The CYP2D6 enzyme activity markers described a gradation of genetic diversity in the ranges from complete deficiency to ultrarapid metabo- geographical space, with allele frequencies forming clines lism, possibly giving rise to profound toxicity of medica- over much of the planet [9,10]. Geographic structuring, tion or therapeutic failure with recommended drug however, is also evident [11,12], which is interpreted by some authors as evidence that a concordant clustering ofgenotypes in major continental or subcontinental clusters Previous genetic studies showed high levels of CYP2D6 is both possible, and useful for medical practice [13]. In polymorphism, both within and between populations [2], particular, the main focus of the challenging debate about and a surprisingly high frequency of null and reduced- individual’s ancestry and drug response [14–16] seems to Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
be the possibility to develop ethnically tailored therapies namely |D0| [24] and R2 [25]. Only polymorphic sites [17–19]. More detailed studies including a high number with minor-allele frequencies higher than 5% in the of populations from different geographic origins, however, region were considered and included in the LD analyses are needed to clarify to what extent the relationship [26]. The significance of associations between poly- between genetics and geography will be of practical use in morphic sites was determined by the Fisher’s exact test and Bonferroni correction, to account for multiplecomparisons. Both measures of LD and Fisher’s exact This study is the first detailed description of CYP2D6 test were calculated using DnaSP 3.99 [27]. The diversity at the global level, based on a mini sequencing phylogenetic relationships of haplotypes were repre- method identifying polymorphism at 12 highly informa- sented in a tree form using the software TCS [28].
tive variable sites, as well as gene deletion and duplica-tions. The systematic use of the same genotyping technique allowed us to generate comparable data for The prediction of enzyme activity corresponding to each all populations sampled. Spatial patterns of CYP2D6 haplotype (Fig. 1) was based on results obtained from variation could be inferred from the analysis of haplo- previously published studies (for reference see http:// www.cypalleles.ki.se/cyp2d6.htm). To assess the differences inCYP2D6 metabolism among regions of the world we used a conventional classification of phenotypes that is basedon the assumption of dominance, in which the phenotype is determined by the most efficient haplotype in the We genotyped 1060 individuals belonging to 52 globally genotype. In this way four phenotypic categories were distributed populations. These Human Genome Diver- recognized, namely poor (PM), intermediate (IM), sity Panel samples were obtained from the Centre extensive (EM) and ultrarapid metabolizers (UM) [29]; d’Etude du Polymorphisme Humain [20]. The sample two decreased-function variants or a combination of one set actually includes 1064 individuals, but four French decreased-function variant and one nonfunctional variant individuals had to be excluded from the analyses because were classified as IM, whereas UM was defined as a we could not amplify their DNAs. In some of theanalyses, the population samples were grouped into eightlarge geographical regions, namely Subsaharan Africa,North Africa, the Middle East, Europe, Central/South Asia, East Asia, Oceania and the Americas. This grouping follows the original Centre d’Etude du PolymorphismeHumain Panel) with the exception of dividing Asia into two regions.
CYP2D6 genotypingAlthough the terminology differs in different studies, in this paper we shall refer to the whole set of polymor- phisms on a chromosome by the term haplotype. Geno- 100 1023 1659 1661 1707 1846 2549 2613-15 2850 2988 3183 4180 Dup activity typing was performed following a recently described protocol based on long PCR and single nucleotide primer extension reaction [21]. Position 1659 was added to the original 11-plex reaction described before. This geno- typing protocol allowed the identification of CYP2D6 variants highly represented in different human popula- tions (i.e. *2, *4, *10, *17, *29, *39 and *41) and variants, even if rare, known to be responsible for low or null metabolic activity (i.e. *3, *6 and *9) [2] as well as the whole gene deletion (*5) and duplications. All haplotypes not showing any of the mutations of interest were CYP2D cluster on chromosome 22 and CYP2D6 inferred haplotypes.
Schematic representation of CYP2D6 gene duplication (a), gene Linkage disequilibrium and network of haplotypes deletion (b), normal CYP2D cluster (c) and CYP2D6 exons (white Haplotypes were inferred from genotypes using the boxes) (d). Inferred haplotypes are named as suggested by theguidelines of Human Cytochrome P450 (CYP) Allele Nomenclature software PHASE v2.1 [22,23]. Linkage disequilibrium Committee. Three new haplotypes (*1661, *4180, *1661xN) were (LD) was tested between each pair of polymorphic sites in each geographical region by calculating two statistics, Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CYP2D6 worldwide genotyping Sistonen et al.
carrier of an active gene duplication on one chromosome some pairwise comparisons and most of the R2 values in conjunction with a functional variant on the other were below 0.3, whereas all tests reached Bonferroni- corrected statistical significance in the other geographicalregions. At the other extreme was Oceania for which estimating LD was impossible because only one mutation We quantified genetic diversity at three levels, namely (1661G > C) was sufficiently polymorphic. The generally between members of the same population, between high values of LD and the significance of the association populations of the same region and between geographical tests allow us to rule out a relevant role of intra-locus regions, by analysis of molecular variance (AMOVA [30]), recombination in shaping CYP2D6 molecular variation, at using Arlequin v2.0 [31]. We typed the CYP2D6 locus in least after the human migration out of Africa.
the same global sample that was analysed for 377autosomal microsatellites short tandem repeats (STRs) This observation is also supported by the network of by Rosenberg et al. [11], and to compare the results we haplotypes shown in Fig. 3a, in which the phylogenetic chose the same grouping of populations. F statistics, relationships between different variants are unambi- analogues of Wright’s F statistics that take the evolu- guously defined with the only exception of one loop tionary distance between individual haplotypes into connecting haplotypes *1 and *39. Above and beyond the account, were estimated. These results were compared clear topology of the tree, another important feature is that the fully functional haplotypes *1 and *2 were the ST values estimated from phenotypic variation.
most frequent variants and widely distributed in different geographical regions. The network also shows that Matrices of geographic (great-circle) distances and derived variants leading to null or impaired metabolic genetic distances were calculated between all pairs of activity such as *4, *10, *17 and *41 could reach a populations [32]. In estimating geographic distances, we relatively high frequency in Europe, East Asia, Africa and considered the likely routes of human migration out of Western Eurasia, respectively. Haplotypes *3 and *9 were Africa, following the criteria by Ramachandran et al. [33].
restricted to Europe, although they did not reach Genetic distances were estimated as pairwise F polymorphic frequencies ( > 1%). Haplotype *6 was also distances. Geographic and genetic distances were com- subpolymorphic, but chromosomes carrying this mutation pared by means of nonparametric Mantel test of matrix were found both in Europe and in the Middle East. The correlation [32,34]. Geographic patterns of CYP2D6 Mozabite population from North Africa had the highest single-haplotype diversity were summarized by a spatial frequency of gene duplications. The high values of autocorrelation statistic, I, estimated by the software functional-variant duplication in the Mozabites and the Near East is consistent with previous studies showingsimilar results in East Africa and the Middle East[35–37]. The Oceanian populations seem to be the outliers in the distribution of haplotype frequencies, showing mostly haplotype *1 and the gene duplication The inferred haplotypes of 1060 individuals genotyped *1xN, the latter associated with high metabolic activity.
for CYP2D6 are shown in Fig. 1 and their frequencies in The only frequent mutation we detected in this region different populations in Table 1. In addition to the was the synonymous substitution 1661G > C in the already known combination of single nucleotide poly- Papuan population. Oceania and America only showed morphisms (SNPs) (http://www.cypalleles.ki.se/cyp2d6.htm), full-functional variants at high frequencies, determining a we identified three new haplotypes that bear only one predominant high metabolic activity of CYP2D6 in these By comparing variation at the coding region, as inferred When pairs of polymorphic sites were tested for the from our 12 polymorphic sites, with the chimpanzee presence of LD, the statistic |D0| was = 1 for 78 (Pan troglodytes) sequence (GenBank accession number comparisons out of 82 with four exceptions in Africa DQ282164), we could identify what can be tentatively and Middle East owing to the presence of the four considered as a candidate ancestral haplotype, namely possible combinations of mutations 1661–2850 (Africa), *4180. This result should be taken cautiously. Indeed, the 100–1661 and 1661–1846 (Middle East) and 1661–4180 chimpanzee sequence contains several differences with (both geographical regions). The values of R2 are shown respect to the human sequence available in GenBank in Fig. 2. Subsaharan Africa displayed the highest (accession number AY545216), most of them occurring in diversity, with eight frequent polymorphic positions. By DNA regions not assayed by the method used for this contrast, only three to six variable sites reached the minor study. As a consequence, reliably rooting the human allele frequency > 5% in the other regions. Africa was the CYP2D6 tree seems to require a more extensive survey of only continent where association was insignificant for its diversity than allowed by 12 SNPs only.
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CYP2D6 haplotype frequencies in single populations and geographically defined groups of populations NE, north-east; SE, south-east; SW, south-west. The haplotype frequencies in geographically defined groups of populations are in bold. Each group consists ofpopulations listed above e.g. SubSaharan Africa includes Biaka Pygmies, Mbuti Pygmies, Mandenka, Yoruba, Bantu NE, Bantu SE, SW and San. The only exception isMozabite which represents alone the geographical region North Africa.
aNumber of chromosomes.
bIncluding one *4B haplotype.
cIncluding haplotypes carrying only 4180G > C, 1661G > C or 1661G > C in duplicated gene.
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CYP2D6 worldwide genotyping Sistonen et al.
more homogeneous for CYP2D6 than for STRs, so thatalmost 100% of the CYP2D6 variation was accounted for by its within-population component (FST = 0.00). The high variance between populations of the Middle East ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ 1661 was entirely due to the presence of the highly divergent and geographically distant sample from North Africa, the Mozabites (28.3% of gene duplications). Oceania seemed to harbour more variation for CYP2D6 than for STR markers but this value was due to the presence of a silent mutation (1661G > C) that does not influence the protein structure; when the analysis was based on the ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ 1661 ∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗ 1661 phenotypes, variance within Oceania was zero. The among-population variance estimated for CYP2D6 in America did not differ from those observed in other regions, whereas in the study by Rosenberg et al. [11] America showed the highest value. By and large, in the AMOVA analysis neither CYP2D6 phenotypes nor haplo-types showed any evident difference from neutral STRs.
Schematic representation of pairwise linkage disequilibrium inSubsaharan Africa, Middle East, Europe, Central/South Asia, East Asiaand America. The colour of the square represents the range of R2 values: black for R2 > 0.6; grey 0.6 Z R2 Z 0.3; white R2 < 0.3.
As a preliminary test, we compared a matrix of normalized Significant values of the association: *P < 0.05; **P < 0.01; ***P < 0.001 after Bonferroni correction. Mozabite population CYP2D6 genetic distances, FST/(1-FST), with the matrix representing North Africa was excluded from this analysis because of of geographic distances between populations by means of Mantel test assuming an out of Africa model. The Mantelpermutation test showed that the correlation is close tosignificance (P = 0.05), but explains a small fraction ofthe total variation (r = 0.18), a result consistent with thelow variances previously observed between populations Phenotypic variationDistribution of CYP2D6 phenotypes predicted from and continents. To test whether the genetic diversity genotypes is shown in Fig. 3b. Europe was characterized observed for CYP2D6 corresponds to that inferred from by the highest frequency of PM phenotypes (8%) and it neutral markers, we compared the CYP2D6 genetic was actually the only continent in which the distribution distance matrix with a genetic distance matrix estimated is approximately bimodal [29]. In all other cases the using 377 autosomal STRs [11]. Positive and statistically distribution was unimodal, but the only common feature significant correlation was observed between the two was the predominance of the EM class. The second most matrices (r = 0.37; P < 0.01) and after controlling for the common metabolic group in North Africa, Oceania, geographic distance (r = 0.21; P < 0.05).
Middle East and America was UM (40, 26, 12 and 8%,respectively). Furthermore, all Oceanian and American The analysis of spatial autocorrelation was repeated individuals belonged to either the UM or the EM class twice: (i) considering all the populations (data not which predicts high metabolic capacity, whereas PMs shown) and (ii) considering only populations in Africa were completely absent. Common decreased-function and Eurasian continent (Fig. 4). Coefficients estimated at variants, *10, *17 and *41, led to higher number of IMs in large distances are affected by the small number of East Asia, Africa and Middle East than in other regions.
samples in Oceania and the Americas, and by their This characteristic has already been described in previous extreme geographical position. We placed more confi- studies with respect to Africa and Asia [2], but the dence in the analysis of the samples of the old world, screening of haplotype *41 allowed us to identify a whose distribution is both denser and more regular. The relevant number of IMs also in the Middle East.
full function and worldwide represented haplotypes *1and *2 showed significant autocorrelation coefficients only in few distance classes, and the overall pattern did When the whole sample was analysed considering seven not suggest any clear interpretation (Fig. 4a). Conversely, regions (Table 2), the differences between regions clear worldwide clines were apparent for haplotypes *4, accounted for 9.3% of the total variance, a result *10, *17, and, in part, *41 (Fig. 4b and c), all of them consistent with estimates based on neutral autosomal associated with null or decreased metabolism. These four markers [9,38,39]. CYP2D6 variances among regions were haplotypes, each showing its maximum frequency in a similar to those estimated from 377 STRs by Rosenberg different region (respectively Europe, East Asia, Sub- et al. [11]. Europe and Central/South Asia seemed to be saharan Africa and Western-Central Asia), decrease in Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CYP2D6 haplotype and phenotype diversity in different geographical regions. (a) CYP2D6 haplotypes are represented in a network. The size of thecircle is proportional to the haplotype frequency in the whole dataset. Mutations separating haplotypes are marked in the figure. Double linescorrespond to gene duplication. The altered enzymatic activity related to a haplotype is represented as follows: increased (m), decreased (k),null ( – ). (b) Frequency of CYP2D6 phenotype classes is shown in different geographical regions. Phenotypes are predicted from genotypesfollowing the model described in Material and methods. UM: ultrarapid metabolizers; EM: extensive metabolizers; IM: intermediate metabolizers;PM: poor metabolizers.
frequency with distance from there, suggesting that these disequilibrium is lowest in Africa and highest in the regions were the likely centers where these haplotypes Americas; and (iv) despite the metabolic role of CYP2D6, making it susceptible to selection, the spatial patterns ofdiversity appear clinal, and very similar to those shown by Previous genetic assessments of the CYP2D6 genevariation have been performed in limited number of All our results suggest that the diversity observed at the populations and often with varying genotyping protocols CYP2D6 locus reflects the same factors affecting variation or interests [2]. To shed light on global variation at this at random genome markers. High CYP2D6 genetic locus, we focused on a detailed molecular study consist- variances within populations are in good agreement with ing of 52 widely distributed populations from all those estimated in studies of neutral markers (reviewed continents. Our study shows that (i) CYP2D6 diversity in [8]). Patterns of LD are consistent with the results of is far greater within than between populations and groups studies suggesting that through their longer evolutionary thereof; (ii) null or low-activity variants occur at high history, African populations have had a greater potential frequencies in various areas of the world; (iii) linkage for recombination to reduce the LD generated by new Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CYP2D6 worldwide genotyping Sistonen et al.
AMOVA, analysis of molecular variance.
aIn Rosenberg et al. [11], number of populations = 6 (Bantu populations together).
mutations or founder effects [40,41]. The broad geo- data). FST values did not differ significantly over 10 graphic cline of CYP2D6 diversity parallels those observed populations originating from Africa, Europe and Asia by Serre and Paabo [10], Ramachandran et al. [33] and, (FST = 0.09 based on sequences, and FST = 0.10 based on with protein markers, by Cavalli-Sforza et al. [42].
SNPs) and in six non-African samples (FST = 0.08 basedon sequences, and FST = 0.09 based on SNPs), but the Typically, differences in the patterns of diversity shown 12 SNPs used for the present study underestimated by different markers are attributed either to chance or to variation in the four African samples (FST = 0.02 based on selection. Inferring selection was not the aim of the sequences, and FST = 0.00 based on SNPs). Therefore, present study; however, the homogeneous geographic we cannot rule out that a fraction, which we cannot distribution of haplotypes *1 and *2 could be regarded as quantify, of African diversity passed undetected in this the result of a long-term selective pressure maintaining study. This may explain why continent-specific haplo- the high frequency of haplotypes coding for a full- types were observed only in Europe, and not in Africa.
function enzyme. Also, local high frequencies of null or Africa, however, is at one extreme of the area affected by reduced-activity haplotypes may indeed be due to the cline, and so greater diversity there could only selective pressures affecting the local populations. Selec- increase the significance of the pattern observed. There- tion, however, can hardly account for the global patterns fore, we cannot rule out that ascertainment bias has of CYP2D6 variation. Indeed, these patterns were very affected some of our results, but the geographic cline similar to those described for neutral markers, both by observed is significant despite, not because, that possible AMOVA and by autocorrelation analysis. This suggests that the global CYP2D6 diversity was largely shaped bythe same combination of gene flow and drift events that As for these spatial patterns, series of founder effects in shaped the diversity of most other genome regions.
the course of an expansion from Africa can explain thecorrelation between genetic and geographic distances Statistics estimated from SNP data may suffer from [33,43]. The autocorrelation patterns observed in this ascertainment bias. The genotyping system used in this study show that CYP2D6 diversity can be described as study allowed us to identify 12 possible mutations of clinal. The overall geographic gradient largely reflects the CYP2D6 gene, together with the whole-gene deletion and gradients shown by the four common haplotypes deter- duplication. Typing of SNPs known to be polymorphic in mining a null or reduced metabolism. Each of these certain populations may lead to underestimation of haplotypes shows its maximum in a different region of the genetic variation in other populations. This is especially true in the case of pharmacogenetic genes, mainlycharacterized in European and North American indivi- Furthermore, we ascertained how many different groups duals of European ancestry. To quantify approximately of populations were supported by CYP2D6 data from this the ascertainment bias, we compared the values of FST study. To this aim, we used Bayesian analysis of estimated from complete coding CYP2D6 sequences, and population structure (BAPS) [44,45], a Bayesian Monte- from 12 SNPs, in samples coming from an analysis of Carlo Markov chain approach, that allowed to assign CYP2D6 sequence diversity (Fuselli et al., unpublished single populations to a nonpredefined number of groups.
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populations of different continents (data not shown).
Therefore, it is hardly surprising that the 11 CYP2D6 clusters do not overlap with those described in any other study focused on human genetic variation at a worldwide level [9,11,14]. Contrary to what has been claimed by some authors [15], there is no guarantee that by analysinga given set of genetic markers, one can obtain information Although the aim of this study was not to replace genotype/phenotype correlation studies, our descriptionof inferred phenotypes may be of significance for pharmacogenetic applications. Altered CYP2D6 meta-bolic activity has been associated with adverse drugreactions [1] or even fatal intoxications [46,47]. In the 1678 3027 3977 4983 6399 7643 8993 10 293 11 340 15 622 majority of cases, metabolism mediated by CYP2D6contributes to inactivation of a drug. For some drugs, however, CYP2D6 catalyses the conversion of a prodrug into an active compound. Thus, adverse reactions can be caused not only by a slower than normal metabolic rate, but also by ultarapid metabolism [48]. Our resultshighlight the relevance of the UM phenotype class represented in each of the eight geographical regionsconsidered in this study, being the second most common group of individuals in North Africa, Middle East,Oceania and America. On the other hand, Europeanpopulations showed the highest frequencies of the PM phenotype, and about one chromosome out of six carriedthe null-function haplotype *4. We, however, cannot exclude an underestimation of population/region-specific 1678 3027 3977 4983 6399 7643 8993 10 293 11 340 15 622 variants (either not tested or unknown) that could conceivably lead to a phenotype other than the one CYP2D6 is of great interest for clinical practice because itis responsible for the metabolism of many commonly useddrugs, and its genetic polymorphism can have a strong effect on the substrate. On the basis of our study, CYP2D6genetic variants related to altered metabolic activity are highly represented in different regions of the world. Thedevelopment of ethnically tailored therapies, however, seems difficult to realize owing to the fact that there areonly few rarely observed region-specific haplotypeschanging the phenotype characterized to date and most 1678 3027 3977 4983 6399 7643 8993 10 293 11 340 15 622 of the variants seem to be geographically dispersed overall continents. Furthermore, population admixture is Spatial autocorrelation analysis in populations from the old world. x-axis: common or quickly increasing in many populations, which higher limit of geographic distance classes (in kilometers). y-axis:Autocorrelation index I. Filled symbols indicate significant values.
should be also taken into account when applying resultsobtained from pharmacogenetic studies [49]. Even ifCYP2D6 polymorphism represents an excellent exampleof the potential clinical implications of pharmacogenetic Sampled populations were clustered using 50 parallel research [50], most of the drug effects and treatment simulation chains over 20 000 iterations. Stability and outcomes are determined by the interaction of multiple convergence of the analysis was ensured by considering genes [51]. Naturally, more knowledge on various factors five replicates of the simulation runs. The analysis affecting the drug response has to be obtained before the showed that 10 clusters out of 11 identified included pharmacogenetic approach can be extensively used in the either some but not all populations of a continent, or Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
CYP2D6 worldwide genotyping Sistonen et al.
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