Distribution of <i>CYP2D6</i> Alleles and Phenotypes in the Brazilian Population

<div><p>Abstract</p><p>The CYP2D6 enzyme is one of the most important members of the cytochrome P450 superfamily. This enzyme metabolizes approximately 25% of currently prescribed medications. The <i>CYP2D6</i> gene presents a high allele heterogeneity that determines great inter-individual variation. The aim of this study was to evaluate the variability of <i>CYP2D6</i> alleles, genotypes and predicted phenotypes in Brazilians. Eleven single nucleotide polymorphisms and <i>CYP2D6</i> duplications/multiplications were genotyped by TaqMan assays in 1020 individuals from North, Northeast, South, and Southeast Brazil. Eighteen <i>CYP2D6</i> alleles were identified in the Brazilian population. The <i>CYP2D6*1</i> and <i>CYP2D6*2</i> alleles were the most frequent and widely distributed in different geographical regions of Brazil. The highest number of <i>CYPD6</i> alleles observed was six and the frequency of individuals with more than two copies ranged from 6.3% (in Southern Brazil) to 10.2% (Northern Brazil). The analysis of molecular variance showed that <i>CYP2D6</i> is homogeneously distributed across different Brazilian regions and most of the differences can be attributed to inter-individual differences. The most frequent predicted metabolic status was EM (83.5%). Overall 2.5% and 3.7% of Brazilians were PMs and UMs respectively. Genomic ancestry proportions differ only in the prevalence of intermediate metabolizers. The IM predicted phenotype is associated with a higher proportion of African ancestry and a lower proportion of European ancestry in Brazilians. PM and UM classes did not vary among regions and/or ancestry proportions therefore unique <i>CYP2D6</i> testing guidelines for Brazilians are possible and could potentially avoid ineffective or adverse events outcomes due to drug prescriptions.</p></div

Pairwise F_ST (95% Confidence Interval) among Brazilian regions and grouped according to color.

<p>Pairwise F_ST (95% Confidence Interval) among Brazilian regions and grouped according to color.</p

<i>CYP2D6</i> allele frequencies in Brazil.

a<p>SNP combination that could not be assigned to a known allele, for more information see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110691#pone.0110691.s003" target="_blank">Table S3</a>.</p><p>χ² = 70.184 and p-value = 0.069 for the comparison of the allele frequencies among the four regions.</p><p><i>CYP2D6</i> allele frequencies in Brazil.</p

Genetic ancestry (mean ± standard deviation) proportions according to CYP2D6 phenotypes.

a<p>P-value for the Kruskal-Wallis One-Way ANOVA.</p>b<p>Significantly higher mean in the pairwise comparisons. FDR adjusted p-values for the IM×PM, IM×EM, and IM×UM comparisons are, respectively: 0.0014, 0.011, and 0.048.</p>c<p>Significantly higher mean in the pairwise comparisons with EM and UM phenotypes. FDR adjusted p-values for the IM×EM, and IM×UM comparisons are, respectively: 0.018, 0.027.</p><p>Genetic ancestry (mean ± standard deviation) proportions according to CYP2D6 phenotypes.</p

CYP2D6 predicted phenotype frequencies according to self-reported color and geographical region.

a<p>Not Determined.</p><p>The Multinomial Log-Linear analysis: self-reported skin color is not associated with the predicted phenotype (p = 0.089); region is not associated with the predicted phenotype (p = 0.467).</p><p>CYP2D6 predicted phenotype frequencies according to self-reported color and geographical region.</p

Copy number variation of the <i>CYP2D6</i> in the Brazilian population.

<p>Copy number variation of the <i>CYP2D6</i> in the Brazilian population.</p

<i>CYP2D6</i> genotyped polymorphisms, inferred alleles and estimated enzyme activity.

<p>Nucleotides in bold are the polymorphic sites.</p><p>Decr = decreased activity.</p><p>Incr = increased activity.</p><p>ND = activity not determined.</p>a<p>According to The Human Cytochrome P450 (CYP) Allele Nomenclature Database <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110691#pone.0110691-Antunes1" target="_blank">[33]</a>.</p>b<p>Deletion of the entire <i>CYP2D6</i> gene.</p><p>SNPs ID numbers are listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110691#pone.0110691.s002" target="_blank">Table S2</a>.</p><p><i>CYP2D6</i> genotyped polymorphisms, inferred alleles and estimated enzyme activity.</p

AMOVA results for the allele frequencies of the sample stratified by region and by self-reported skin color.

<p>*Four Brazilian regions were considered: North, Northeast, Southeast, and South.</p><p>**Three skin color categories were considered: Black, Brown and White.</p><p>AMOVA results for the allele frequencies of the sample stratified by region and by self-reported skin color.</p