de Biología Tropical ISSN Impreso: 0034-7744 ISSN electrónico: 2215-2075

Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans

Carolina Céspedes-Garro, Gerardo Jiménez-Arce, María-Eugenia G. Naranjo, Ramiro Barrantes, Adrián LLerena, Autor institucional



CYP2D6 differences have already been demonstrated within Latin American populations by the CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics (RIBEF, as per the acronym in Spanish). However, within the population of Costa Rica, no research has been conducted until now, even though this population has a trihybrid component ancestry that represents an interesting condition. Thus, the present study was aimed to determine the frequency of Ultra-rapid Metabolizers (UMs) and Poor Metabolizers (PMs) in a Costa Rican population, as well as to determine whether there are differences in the CYP2D6-predicted phenotype frequencies among three Costa Rican groups with different ethnic backgrounds. Additionally, these frequencies of PMs and UMs obtained were compared with Ibero-American populations published data. Finally, we also aimed to describe allele frequencies among different Costa Rican ethnic groups. This research has been undertaken within the framework of the RIBEF CEIBA Consortium studies on Latin American populations. A total of 385 individuals were included in the study: 139 mestizos, 197 Amerindians, and 49 Afro-Caribbeans. CYP2D6 genotypes were determined by XL-PCR and Real-Time PCR. The CYP2D6 variant alleles *2, *3, *4, *5, *6, *10, *17, *29, *35 and *41 were also determined. For the entire Costa Rican population, the frequency of PMs and UMs was 6% and 6.5%, respectively. The percentage of UMs in the mestizo population was higher than in the Amerindian population. CYP2D6 UMs vary from 3.6% to 10.1% and PMs from 1.4% to 10.2% among three Costa Rican groups. The highest frequencies of UMs (10.1%) and PMs (10.2%) were found in the mestizo and Amerindian populations, respectively. In conclusion, the frequencies of UMs and PMs for CYP2D6 varied widely across the mestizo, Amerindian and Afro-Caribbean Costa Rican populations. Future research in this population should be oriented to identify new CYP2D6 variants through sequencing methods, as well as to determine CYP2D6 phenotype, in order to establish the phenotype-genotype relation. Finally, further studies involving genetic markers of ancestry are needed in the Costa Rican population.


Carolina Céspedes-Garro1,2, Gerardo Jiménez-Arce1, María-Eugenia G. Naranjo2, Ramiro Barrantes1* and Adrián LLerena2*; CEIBA Consortium of the Ibero-American Network of Pharmacogenetics & Pharmacogenomics RIBEF.



CYP2D6, Costa Rica, Amerindian, Afro-Caribbean, mestizo, populations, Poor Metabolizers, Ultra-rapid Metabolizers


Albuquerque, J., Ribeiro, C., Naranjo, M. E., Llerena, A., Grazina, M., & CEIBA.FP Consortium. (2013). Characterization of CYP2D6 genotypes and metabolic profiles in the Portuguese population: pharmacogenetic implications. Personalized Medicine, 10(7), 709-718.

Arias, T. D., Jorge, L., Lee, D., Guerrero de Solís, N., Escobar, J., Barrantes, R., & Inaba, T. (1986). Biotransformation of sparteine in the Cuna American Indians of Panama. Revista médica de Panamá, 11(3), 199-209.

Arias, T. D., Jorge, L. F., Lee, D., Barrantes, R., & Inaba, T. (1988). The oxidative metabolism of sparteine in the Cuna Amerindians of Panama: absence of evidence for deficient metabolizers. Clinical Pharmacology and Therapeutics, 43(4), 456-465.

Azofeifa, J., Hahn, M., Ruiz, E., Hummerich, L., Morales, A. I., Jiménez, G., & Barrantes, R. (2004). The STR polymorphism (AAAAT)n within the intron 1 of the tumor protein 53 (TP53) locus in 17 populations of different ethnic groups of Africa, America, Asia and Europe. Revista de Biología Tropical, 52(3), 645-657.

Bailliet, G., Santos, M. R., Alfaro, E. L., Dipierri, J. E., Demarchi, D. A., Carnese, F. R., & Bianchi, N. O. (2007). Allele and genotype frequencies of metabolic genes in Native Americans from Argentina and Paraguay. Mutation Research, 627(2), 171-177.

Barrantes, R., Smouse, P. E., Neel, J. V., Mohrenweiser, H. W., & Gershowitz, H. (1982). Migration and genetic infrastructure of the Central American Guaymi and their affinities with other tribal groups. American Journal of Physical Anthropology, 58(2), 201-214.

Barrantes, R. (1989). Biodemografía de las poblaciones amerindias de Costa Rica. Vínculos, 15, 59-68.

Barrantes, R., Smouse, P. E., Mohrenweiser, H. W., Gershowitz, H., Azofeifa, J., Arias, T. D., & Neel, J. V. (1990). Microevolution in lower Central America: genetic characterization of the Chibcha-speaking groups of Costa Rica and Panama, and a consensus taxonomy based on genetic and linguistic affinity. American Journal of Human Genetics, 46(1), 63-84.

Barrantes, R. (1993a). Diversidad genética y mezcla racial en los amerindios de Costa Rica y Panamá. Revista de Biología Tropical, 41(3), 379-384.

Barrantes, R. (1993b). Estructura de poblaciones. In Evolución en el trópico: los amerindios de Costa Rica y Panamá (pp. 51-85). San José, Costa Rica: Editorial de la Universidad de Costa Rica.

Bieber, H., Bieber, S. W., Rodewald, A., & Barrantes, R. (1996). Microevolution and genetic affinities among six Amerindian tribes of lower Central America: comparative genetic study of serum proteins. Human Biology, 68(6), 929-953.

Bradford, L. D. (2002). CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics, 3(2), 229-243.

Casner, P. R. (2005). The effect of CYP2D6 polymorphisms on dextromethorphan metabolism in Mexican Americans. Journal of Clinical Pharmacology, 45(11), 1230-1235.

Crescenti, A., Mas, S., Gassó, P., Baiget, M., Bernardo, M., & Lafuente, A. (2007). Simultaneous genotyping of CYP2D6*3, *4, *5 and *6 polymorphisms in a Spanish population through multiplex long polymerase chain reaction and minisequencing multiplex single base extension analysis. Clinical and Experimental Pharmacology & Physiology, 34(10), 992-997.

Crews, K. R., Gaedigk, A., Dunnenberger, H. M., Klein, T. E., Shen, D. D., Callaghan, J. T., Kharasch, E. D., & Skaar, T. C. (2012). Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clinical Pharmacology and Therapeutics, 91(2), 321-326.

CYP Alleles Nomenclature Database. (2013). The Human Cytochrome P450 (CYP) Allele Nomenclature Database. Retrieved from

De Andrés, F., Sosa-Macías, M., Lazalde-Ramos, B. P., Naranjo, M. E. G., Tarazona-Santos, E., Llerena, A., & CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics and Pharmacogenomics RIBEFa. (2013). Evaluation of drug-metabolizing enzyme hydroxylation phenotypes in Hispanic populations: the CEIBA cocktail. Drug Metabolism and Drug Interactions, 28(3), 135-146. doi:10.1515/dmdi-2013-0020

Dorado, P., Cáceres, M. C., Pozo-Guisado, E., Wong, M. L., Licinio, J., & Llerena, A. (2005). Development of a PCR-based strategy for CYP2D6 genotyping including gene multiplication of worldwide potential use. BioTechniques, 39(4), 571-574.

Dorado, P., Heras, N., Machín, E., Hernández, F., Teran, E., & Llerena, A. (2012). CYP2D6 genotype and dextromethorphan hydroxylation phenotype in an Ecuadorian population. European Journal of Clinical Pharmacology, 68(5), 637-644.

Estevez, F., Giusti, M., Parrillo, S., & Oxandabarat, J. (1997). Dextromethorphan O-demethylation polymorphism in the Uruguayan population. European Journal of Clinical Pharmacology, 52(5), 417-418.

Fohner, A., Muzquiz, L. I., Austin, M. A., Gaedigk, A., Gordon, A., Thornton, T., Rieder, M. J., Pershouse, M. A., Putnam, E. A., Howlett, K., Beatty, P., Thummel, K. E., & Woodahl, E. L. (2013). Pharmacogenetics in American Indian populations: analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes. Pharmacogenetics and Genomics, 23(8), 403-414. doi:10.1097/FPC.0b013e3283629ce9

Gaedigk, A., Bradford, L., Marcucci, K., & Leeder, J. (2002). Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans. Clinical Pharmacology and Therapeutics, 72(1), 76-89.

Gaedigk, A., Simon, S. D., Pearce, R. E., Bradford, L. D., Kennedy, M. J., & Leeder, J. S. (2008). The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clinical Pharmacology and Therapeutics, 83(2), 234-242.

Gaedigk, A., Isidoro-García, M., Pearce, R. E., Sánchez, S., García-Solaesa, V., Lorenzo-Romo, C., Gonzalez-Tejera, G., & Corey, S. (2010). Discovery of the nonfunctional CYP2D6 31 allele in Spanish, Puerto Rican, and US Hispanic populations. European Journal of Clinical Pharmacology, 66(9), 859-864.

González, I., Peñas-Lledó, E. M., Pérez, B., Dorado, P., Alvarez, M., & Llerena, A. (2008). Relation between CYP2D6 phenotype and genotype and personality in healthy volunteers. Pharmacogenomics, 9(7), 833-840.

Griman, P., Moran, Y., Camargo, M., & Chiurillo, M. (2009). Caraterización de las variantes alélicas del citocromo CYP2D6 en la población de la región centroccidental de Venezuela. Acta Biológica Colombiana, 14(1), 195-202.

Griman, P., Moran, Y., Valero, G., Loreto, M., Borjas, L., & Chiurillo, M. A. (2012). CYP2D6 gene variants in urban/admixed and Amerindian populations of Venezuela: pharmacogenetics and anthropological implications. Annals of Human Biology, 39(2), 137-142.

Herrmann, F., Salazar-Sánchez, L., Schuster, G., Jiménez-Arce, G., Grimm, R., Gómez, X., Chavez, V., & Schrøder, W. (2002). Molecular markers in the genes for FV (FVL. FV HR2, FVIVS 16), MTHFR, prothrombin and ACE in Amerindians and Africans from Costa Rica. Gene Diagnosis of Inherited Bleeding Disorders, 203-220.

Hicks, J. K., Swen, J. J., Thorn, C. F., Sangkuhl, K., Kharasch, E. D., Ellingrod, V. L., Skaar, T. C., Müller, D. J., Gaedigk, A., & Stingl, J. C. (2013). Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clinical Pharmacology and Therapeutics, 93(5), 402-408. doi:10.1038/clpt.2013.2

Ingelman-Sundberg, M. (2005). Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. The Pharmacogenomics Journal, 5(1), 6-13.

Isaza, C. A., Henao, J., López, A. M., & Cacabelos, R. (2000). Isolation, sequence and genotyping of the drug metabolizer CYP2D6 gene in the Colombian population. Methods and Findings in Experimental and Clinical Pharmacology, 22(9), 695-705.

Jorge, L. F., & Arias, T. D. (1995). Human biodiversity and its effects on the pharmacological variability: CYP2D6 and NAT2 enzymes in Amerind populations of Panama, Colombia and Costa Rica. Revista Médica de Panamá, 20(3), 98-107.

Jorge, L. F., Eichelbaum, M., Griese, E. U., Inaba, T., & Arias, T. D. (1999). Comparative evolutionary pharmacogenetics of CYP2D6 in Ngawbe and Embera Amerindians of Panama and Colombia: role of selection versus drift in world populations. Pharmacogenetics, 9(2), 217-228.

Kohlrausch, F. B., Gama, C. S., Lobato, M. I., Belmonte-de-Abreu, P., Gesteira, A., Barros, F., Carracedo, A., & Hutz, M. H. (2009). Molecular diversity at the CYP2D6 locus in healthy and schizophrenic southern Brazilians. Pharmacogenomics, 10(9), 1457-1466.

Llerena, A., Edman, G., Cobaleda, J., Benítez, J., Schalling, D., & Bertilsson, L. (1993). Relationship between personality and debrisoquine hydroxylation capacity. Suggestion of an endogenous neuroactive substrate or product of the cytochrome P4502D6. Acta Psychiatrica Scandinavica, 87(1), 23-28.

Llerena, A., Dorado, P., & Peñas-Lledó, E. M. (2009). Pharmacogenetics of debrisoquine and its use as a marker for CYP2D6 hydroxylation capacity. Pharmacogenomics, 10(1), 17-28.

Llerena, A., Dorado, P., Ramírez, R., González, I., Alvarez, M., Peñas-Lledó, E. M., Pérez, B., & Calzadilla, L. R. (2012). CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans. The Pharmacogenomics Journal, 12(2), 176-183.

Llerena, A., Dorado, P., Ramírez, R., Calzadilla, L. R., Peñas-Lledó, E., Alvarez, M., Naranjo, M. E., González, I., Pérez, B., & CEIBA Consortium of the Ibero-American Network of Pharmacogenetics & Pharmacogenomics RIBEF. (2013). CYP2D6 -1584C>G promoter polymorphism and debrisoquine ultrarapid hydroxylation in healthy volunteers. Pharmacogenomics, 14(16), 1973-1977. doi:10.2217/pgs.13.181

López, M., Guerrero, J., Jung-Cook, H., & Alonso, M. E. (2005). CYP2D6 genotype and phenotype determination in a Mexican Mestizo population. European Journal of Clinical Pharmacology, 61(10), 749-754.

Løvlie, R., Daly, A. K., Molven, A., Idle, J. R., & Steen, V. M. (1996). Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene. FEBS Letters, 392(1), 30-34.

Luo, H. R., Gaedigk, A., Aloumanis, V., & Wan, Y. J. Y. (2005). Identification of CYP2D6 impaired functional alleles in Mexican Americans. European Journal of Clinical Pharmacology, 61(11), 797-802.

Madrigal, L. (2006). The Afro-Caribbean population in Limón, Costa Rica. In Human Biology of Afro-Caribbean populations (pp. 176-185). New York, USA: Cambridge University Press.

Mendoza, R., Wan, Y. J., Poland, R. E., Smith, M., Zheng, Y., Berman, N., & Lin, K. M. (2001). CYP2D6 polymorphism in a Mexican American population. Clinical Pharmacology and Therapeutics, 70(6), 552-560.

Montané-Jaime, L. K., Lalla, A., Steimer, W., & Gaedigk, A. (2013). Characterization of the CYP2D6 gene locus and metabolic activity in Indo- and Afro-Trinidadians: discovery of novel allelic variants. Pharmacogenomics, 14(3), 261-276. doi:10.2217/pgs.12.207

Morera, B., Barrantes, R., & Marin-Rojas, R. (2003). Gene admixture in the Costa Rican population. Annals of Human Genetics, 67(1), 71-80.

Morera, B., & Barrantes, R. (2004). Is the Central Valley of Costa Rica a genetic isolate? Revista de Biología Tropical, 52(3), 629-644.

Muñoz, S., Vollrath, V., Vallejos, M. P., Miquel, J. F., Covarrubias, C., Raddatz, A., & Chianale, J. (1998). Genetic polymorphisms of CYP2D6, CYP1A1 and CYP2E1 in the South-Amerindian population of Chile. Pharmacogenetics, 8(4), 343-351.

Peñas-Lledó, E. M., Dorado, P., Pacheco, R., González, I., & Llerena, A. (2009). Relation between CYP2D6 genotype, personality, neurocognition and overall psychopathology in healthy volunteers. Pharmacogenomics, 10(7), 1111-1120.

Peñas-Lledó, E. M., Dorado, P., Agüera, Z., Gratacós, M., Estivill, X., Fernández-Aranda, F., & Llerena, A. (2012). CYP2D6 polymorphism in patients with eating disorders. The Pharmacogenomics Journal, 12(2), 173-175.

Reich, D., Patterson, N., Campbell, D., Tandon, A., Mazieres, S., Ray, N., Parra, M. V., Rojas, W., Duque, C., Mesa, N., García, L. F., Triana, O., Blair, S., Maestre, A., Dib, J. C., Bravi, C. M., Bailliet, G., Corach, D., Hünemeier, T., Bortolini, M. C., Salzano, F. M., Petzl-Erler, M. L., Acuña-Alonzo, V., Aguilar-Salinas, C., Canizales-Quinteros, S., Tusié-Luna, T., Riba, L., Rodríguez-Cruz, M., López-Alarcón, M., Coral-Vázquez, R., Canto-Cetina, T., Silva-Zolezzi, I., Fernández-López, J. C., Contreras, A. V., Jiménez-Sánchez, G., Gómez-Vázquez, M. J., Molina, J., Carracedo, A., Salas, A., Gallo, C., Poletti, G., Witonsky, D. B., Alkorta-Aranburu, G., Sukernik, R. I., Osipova, L., Fedorova, S. A., Vasquez, R., Villena, M., Moreau, C., Barrantes, R., Pauls, D., Excoffier, L., Bedoya, G., Rothhammer, F., Dugoujon, J. M., Larrouy, G., Klitz, W., Labuda, D., Kidd, J., Kidd, K., Di Rienzo, A., Freimer, N. B., Price, A. L., & Ruiz-Linares, A. (2012). Reconstructing Native American population history. Nature, 488(7411), 370-374.

Rodeiro, I., Remírez-Figueredo, D., García-Mesa, M., Dorado, P., Llerena, A., & CEIBA.FP Consortium of the Ibero-American Network of Pharmacogenetics and Pharmacogenomics RIBEF. (2012). Pharmacogenetics in Latin American populations: regulatory aspects, application to herbal medicine, cardiovascular and psychiatric disorders. Drug Metabolism and Drug Interactions, 27(1), 57-60.

Ruiz-Narváez, E. A., Santos, F. R., Carvalho-Silva, D. R., Azofeifa, J., Barrantes, R., & Pena, S. D. J. (2005). Genetic variation of the Y chromosome in Chibcha-speaking Amerindians of Costa Rica and Panama. Human Biology, 77(1), 71-91.

Sans, M. (2000). Admixture studies in Latin America: from the 20th to the 21st century. Human Biology, 72(1), 155-177.

Santos, M., Ward, R. H., & Barrantes, R. (1994). mtDNA variation in the Chibcha Amerindian Huetar from Costa Rica. Human Biology, 66(6), 963-977.

Segura-Wang, M., Raventós, H., Escamilla, M., & Barrantes, R. (2010). Assessment of genetic ancestry and population substructure in Costa Rica by analysis of individuals with a familial history of mental disorder. Annals of Human Genetics, 74(6), 516-524.

Silveira, V. D. S., Canalle, R., Scrideli, C. A., Queiroz, R. G. de P., & Tone, L. G. (2009). Polymorphisms in genes encoding drugs and xenobiotic metabolizing enzymes in a Brazilian population. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals, 14(2), 111-117.

Sosa-Macías, M., Elizondo, G., Flores-Pérez, C., Flores-Pérez, J., Bradley-Alvarez, F., Alanis-Bañuelos, R. E., & Lares-Asseff, I. (2006). CYP2D6 genotype and phenotype in Amerindians of Tepehuano origin and Mestizos of Durango, Mexico. Journal of Clinical Pharmacology, 46(5), 527-536.

Sosa-Macías, M., Dorado, P., Alanis-Bañuelos, R. E., Llerena, A., & Lares-Asseff, I. (2010). Influence of CYP2D6 deletion, multiplication, -1584C-->G, 31G-->A and 2988G-->a gene polymorphisms on dextromethorphan metabolism among Mexican tepehuanos and mestizos. Pharmacology, 86(1), 30-36.

Thompson, E. A., Neel, J. V., Smouse, P. E., & Barrantes, R. (1992). Microevolution of the Chibcha-speaking peoples of lower Central America: rare genes in an Amerindian complex. American Journal of Human Genetics, 51(3), 609-626.

Wang, S., Lewis, C. M., Jakobsson, M., Ramachandran, S., Ray, N., Bedoya, G., Rojas, W., Parra, M. V., Molina, J. A., Gallo, C., Mazzotti, G., Poletti, G., Hill, K., Hurtado, A. M., Labuda, D., Klitz, W., Barrantes, R., Bortolini, M. C., Salzano, F. M., Petzl-Erler, M. L., Tsuneto, L. T., Llop, E., Rothhammer, F., Excoffier, L., Feldman, M. W., Rosenberg, N. A., & Ruiz-Linares, A. (2007). Genetic variation and population structure in native Americans. PLoS Genetics, 3(11), e185.

Wang, S., Ray, N., Rojas, W., Parra, M. V., Bedoya, G., Gallo, C., Poletti, G., Mazzotti, G., Hill, K., Hurtado, A. M., Camrena, B., Nicolini, H., Klitz, W., Barrantes, R., Molina, J. A., Freimer, N. B., Bortolini, M. C., Salzano, F. M., Petzl-Erler, M. L., Tsuneto, L. T., Dipierri, J. E., Alfaro, E. A., Bailliet, G., Bianchi, N. O., Llop, E., Rothhammer, F., Excoffier, L., & Ruiz-Linares, A. (2008). Geographic patterns of genome admixture in Latin American Mestizos. PLoS Genetics, 4(3), e1000037.


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