title: Lessons from Cuba for Global Precision Medicine: CYP2D6 Genotype Is Not a Robust Predictor of CYP2D6 Ultrarapid Metabolism.
abstract: A long-standing question and dilemma in precision medicine is whether and to what extent genotyping or phenotyping drug metabolizing enzymes such as CYP2D6 can be used in real-life global clinical and societal settings. Although in an ideal world using both genotype and phenotype biomarkers are desirable, this is not always feasible for economic and practical reasons. Moreover, an additional barrier for clinical implementation of precision medicine is the lack of correlation between genotype and phenotype, considering that most of the current methods include only genotyping. Thus, the present study evaluated, using dextromethorphan as a phenotyping probe, the relationship between CYP2D6 phenotype and CYP2D6 genotype, especially for the ultrarapid metabolizer (UM) phenotype. We report in this study, to the best of our knowledge, the first comparative clinical pharmacogenomics study in a Cuban population sample (N = 174 healthy volunteers) and show that the CYP2D6 genotype is not a robust predictor of the CYP2D6 ultrarapid metabolizer (mUM) status in Cubans. Importantly, the ultrarapid CYP2D6 phenotype can result in a host of health outcomes, such as drug resistance associated with subtherapeutic drug concentrations, overexposure to active drug metabolites, and altered sensitivity to certain human diseases by virtue of altered metabolism of endogenous substrates of CYP2D6. Hence, phenotyping tests for CYP2D6 UMs appear to be a particular necessity for precision medicine in the Cuban population. Finally, in consideration of ethical and inclusive representation in global science, we recommend further precision medicine biomarker 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: Pedro
authors.initials: P
authors.lastname: Dorado
authors.affiliation: 2 Centro de Salud Mental, Área de Salud Zafra-Llerena, Servicio Extremeño de Salud , Llerena, Spain .
authors.forename: Idilio
authors.initials: I
authors.lastname: González
authors.affiliation: 1 CICAB, Clinical Research Centre, Extremadura University Hospital and Medical School , Badajoz, Spain .
authors.forename: María Eugenia G
authors.initials: ME
authors.lastname: Naranjo
authors.affiliation: 1 CICAB, Clinical Research Centre, Extremadura University Hospital and Medical School , Badajoz, Spain .|3 Department of Analytical Chemistry and Food Technology, Faculty of Pharmacy, University of Castilla-La Mancha , Albacete, Spain .
authors.forename: Fernando
authors.initials: F
authors.lastname: de Andrés
authors.affiliation: 1 CICAB, Clinical Research Centre, Extremadura University Hospital and Medical School , Badajoz, Spain .
authors.forename: Eva María
authors.initials: EM
authors.lastname: Peñas-Lledó
authors.affiliation: 4 Centro Comunitario de Salud Mental Habana Vieja , La Habana, Cuba .
authors.forename: Luis Ramón
authors.initials: LR
authors.lastname: Calzadilla
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: D000328:Adult; D003462:Cuba; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010597:Pharmacogenetics / Q000379:methods; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods*
chemical_list: D019389:Cytochrome P-450 CYP2D6
keywords: biomarkers; developing world omics; diagnostic medicine; innovation systems; personalized medicine; system diagnostics