title: To Genotype or Phenotype for Personalized Medicine? CYP450 Drug Metabolizing Enzyme Genotype-Phenotype Concordance and Discordance in the Ecuadorian Population.
abstract: Genetic variations within the cytochrome P450 (CYP450) superfamily of drug metabolizing enzymes confer substantial person-to-person and between-population differences in pharmacokinetics, and by extension, highly variable clinical effects of medicines. In this context, "personalized medicine," "precision medicine," and "stratified medicine" are related concepts attributed to what is essentially targeted therapeutics and companion diagnostics, aimed at improving safety and effectiveness of health interventions. We report here, to the best of our knowledge, the first comparative clinical pharmacogenomics study, in an Ecuadorian population sample, of five key CYP450s involved in drug metabolism: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In 139 unrelated, medication-free, and healthy Ecuadorian subjects, we measured the phenotypic activity of these drug metabolism pathways using the CEIBA multiplexed phenotyping cocktail. The subjects were genotyped for each CYP450 enzyme gene as well. Notably, based on the CYP450 metabolic phenotypes estimated by the genotype data, 0.75% and 3.10% of the subjects were genotypic poor metabolizers (gPMs) for CYP2C19 and CYP2D6, respectively. Additionally, on the other extreme, genotype-estimated ultrarapid metabolizer (gUMs) phenotype was represented by 15.79% of CYP2C19, and 5.43% of CYP2D6. There was, however, considerable discordance between directly measured phenotypes (mPMs and mUMs) and the above genotype-estimated enzyme phenotypes. For example, among individuals genotypically carrying enhanced activity alleles (gUMs), many showed a lower actual drug metabolism capacity than expected by their genotypes, even lower than individuals with reduced or no activity alleles. In conclusion, for personalized medicine in the Ecuadorian population, we recommend CYP450 multiplexed phenotyping, or genotyping and phenotyping in tandem, rather than CYP450 genotypic tests alone. Additionally, we recommend, in consideration of equity, ethical, and inclusive representation in global science, further precision medicine research and funding in support of neglected or understudied populations worldwide.
authors.affiliation: 1 CICAB Clinical Research Centre, Extremadura University Hospital and Medical School , Badajoz, Spain .
authors.forename: Fernando
authors.initials: F
authors.lastname: De Andrés
authors.affiliation: 2 Colegio de Ciencias de la Salud, Universidad San Francisco de Quito , Quito, Ecuador .
authors.forename: Santiago
authors.initials: S
authors.lastname: Terán
authors.affiliation: 3 Facultad de Ciencias Médicas, Universidad Estatal de Guayaquil , Guayaquil, Ecuador .
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernández
authors.affiliation: 2 Colegio de Ciencias de la Salud, Universidad San Francisco de Quito , Quito, Ecuador .
authors.forename: Enrique
authors.initials: E
authors.lastname: Terán
authors.affiliation: 1 CICAB Clinical Research Centre, Extremadura University Hospital and Medical School , Badajoz, Spain .
authors.forename: Adrián
authors.initials: A
authors.lastname: LLerena
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods*
chemical_list: D015415:Biomarkers; D003577:Cytochrome P-450 Enzyme System
keywords: biomarkers; developing world omics; diagnostic medicine; innovation systems; personalized medicine; systems diagnostics