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Relationships between CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 metabolic phenotypes and genotypes in a Nicaraguan Mestizo population

Abstract

Interethnic variability in the drug-metabolizing capacity of CYP450 enzymes may lead to discrepancies in the relationship between genotypes and phenotypes worldwide. The present study was aimed to analyze for the first time whether there is a relationship between clinically relevant CYP450 genetic polymorphisms and their drug oxidation capacity (metabolic phenotype) in a population of healthy Nicaraguan volunteers. Two hundred and twelve participants were genotyped for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and their actual metabolic phenotype (evaluated by the Metabolic Ratio, MR) was analyzed by using the CEIBA cocktail approach. The results showed the wide interindividual variability in all the studied enzymes and a significant difference (p < 0.004) in the activity of CYP1A2 between male and female subjects. The number of CYP2C19 (p < 0.0001) and CYP2D6 (p < 0.0001) active alleles were shown inversely correlated with their corresponding MR, although there were marked genotype-phenotype discrepancies. There was an actual enzyme capacity overlapping (MR) between genotypically Poor (gPMs) and Extensive Metabolizers (gEMs) of 3.14% subjects for CYP2D6 and 0.94% for CYP2C9. Similarly, there was an overlapping for metabolic phenotypes of 11.48% of genotypically ultrarapid metabolizers (gUMs) for CYP2C19 and 2.09% for CYP2D6 and gEMs. Therefore, the current approach for metabolic phenotype prediction based just on genotype does not predict properly for all individuals within this Nicaraguan Mestizo population, thus representing a potential barrier for the clinical implementation of personalized medicine in this region. However, it is necessary to improve the prediction of phenotype from genotype in order to improve the pharmacogenetic implementation in populations with specific ethnic backgrounds.

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Fig. 1: The relationship between the phenotype evaluated by the Test-Drug Metabolic Ratio and the phenotype “predicted” from genotype (Activity Score).
Fig. 2: Relationship among predicted phenotype by genotype (activity score) and metabolic ratios (log10) for every CYP450 analyzed in the Nicaraguan population studied.
Fig. 3: Probit plots and frequency distributions of MRs (log10) of all the volunteers phenotyped for CYP1A2 (n = 209), CYP2C9 (n = 209), CY2C19 (n = 209), CYP2D6 (n = 191), and CYP3A4 (n = 89).

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Acknowledgements

Supported by Junta Extremadura-AEXCID (18IA003) to SIFF and RIBEF (Iberoamerican Network of Pharmacogenetics and Pharmacogenomics) (www.redribef.com).

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de Andrés, F., Altamirano-Tinoco, C., Ramírez-Roa, R. et al. Relationships between CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 metabolic phenotypes and genotypes in a Nicaraguan Mestizo population. Pharmacogenomics J 21, 140–151 (2021). https://doi.org/10.1038/s41397-020-00190-9

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