Genetic variability of <i>CYP2D6</i>, <i>CYP2B6</i>, <i>CYP2C9</i> and <i>CYP2C19</i> genes across the Italian Peninsula

<b>Background:</b> Environmental conditions and past migratory events may have shaped genetic heterogeneity of clinically relevant enzymes involved in the phase I metabolism of the most common therapeutic drugs. <b>Aim:</b> To investigate the genetic variability of <i>CYP2D6</i>, <i>CYP2B6</i>, <i>CYP2C19</i> and <i>CYP2C9</i> across the Italian Peninsula, by sampling only ancestrally and geographically homogeneous individuals from northern, central and southern Italy. <b>Subjects and methods:</b> A total of 25 SNPs were genotyped in 174 unrelated Italian individuals by means of multiplex PCR and minisequencing reactions. <i>CYP2D6</i> genotypic data were used to predict phenotypes and the phylogenetic relationships among reconstructed haplotypes were represented by means of a Median Joining Network. <b>Results:</b> Pairwise Fisher Exact tests revealed significant differences between northern and southern Italy in the distribution of <i>CYP2C19</i> genotypes, with the <i>CYP2C19*2</i> allele appearing over-represented in northern Italy. Likewise, significant differences in the distribution of <i>CYP2D6</i> genotypes (*4/*3, *4/*4 and *6/*4) responsible for the poor metabolizer phenotype were observed in northern with respect to both central and southern Italy. <b>Conclusions:</b> The north–south structuring pattern showed by <i>CYP2D6</i> and <i>CYP2C19</i> underline how a deeper knowledge of the geographic distribution of alleles may improve clinical practice and help to avoid hypothetical bias in drug trials.