Updating the study of pharmacogenetic polymorphisms in the Portuguese Roma

Polymorphisms in genes coding for drug-metabolizing enzymes (DME) are major players in interindividual variability in drug response. Among DME, cytochrome P450 family 2, subfamily D, polypeptide 6, CYP2D6, is one of the most important, because it is involved in metabolism of 25% to 30% of all prescribed drugs, including antidepressants, antipsychotics, anti-arrhythmics, β-blockers, cancer chemotherapeutics, among others. The enzymatic activity of CYP2D6 varies widely among individuals, mainly due to functional genetic variations at the encoding gene, resulting in significant clinical consequences for drug metabolism and individual risk of adverse events or drug efficacy. Although many populations have been studied regarding the CYP2D6, there are still populations scarcely studied, such as the Roma from Europe. The Roma represent an interesting population case study that is still understudied in many aspects. During the Gypsy diaspora, it was normal the occurrence of group fragmentation into smaller communities, but still maintaining endogamous practices. From a genetic point of view, this leads to high genetic drift effects, reduced genetic diversity, high linkage disequilibrium and limited gene flow between these groups. Therefore, due to these traits and to the scarcity of Pharmacogenetic studies in this population, in this present study, we intended to characterize the Portuguese Roma for Single Nucleotide Polymorphisms (SNPs), relevant from the Pharmacogenetics point of view, to evaluate if the Roma show any peculiarity regarding drug response, in comparison with the host population. In that sense, 56 samples from Portuguese Roma were analysed by SNaPshot reaction, designed and optimized to detect 11 SNPs located within the CYP2D6 gene, known to influence drug response. For comparative analysis, data from previous studies in the Portuguese host population was used, as well from several populations around the world, to put the data obtained in a worldwide context. For the variations studied, only one SNP revealed significant deviation from the Hardy – Weinberg expectation, even after the Bonferroni correction, which was the 4180 G>C. Comparatively to the Portuguese host population, the Roma showed some differences, especially an increased frequency of the CYP2D6*4, an allele implying null enzymatic activity. Regarding the theoretical metabolic profiles, differences were found, especially the IM and PM profiles. FCUP 7 Updating the study of pharmacogenetic polymorphisms in the Portuguese Roma Even though we studied a set of SNPs considered to be of high resolution, further studies are needed to deepen the results here obtained, preferably with the joint analysis of biochemical assessment of enzymatic activity. Also, new studies are needed, not only in the Portuguese host population, but also in other European populations, with a larger number of SNPs, so that the knowledge regarding these populations and further comparative analysis can allow to extract more inferences relevant from the perspective of Pharmacogenetics. With the development of the present study, we have contributed to deepening the characterization of Roma populations, helping to further the knowledge from the pharmacogenetic point of view regarding the CYP2D6, as well as to enhance the importance of Pharmacogenetics in the clinical setting.