Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans / Antecedentes étnicos y polimorfismo genético del CYP2D6 en los costarricenses

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.

El Consorcio de la Red Iberoamericana de Farmacogenética CEIBA.FP ha demostrado que existen diferencias en cuanto a CYP2D6 en las poblaciones latinoamericanas. Sin embargo, hasta ahora, se sabe poco de este gen de importancia farmacogenética en la población de Costa Rica, la cual tiene una ancestría trihíbrida. El presente estudio tiene como objetivos: determinar la frecuencia de los fenotipos extrapolados de CYP2D6 en una población costarricense y determinar si existen diferencias en cuanto a las frecuencias de metabolizadores lentos (PMs) y ultra-rápidos (UMs) entre tres grupos con distinto origen étnico. Adicionalmente, las frecuencias de PMs y UMs obtenidas en este estudio fueron comparadas con datos de poblaciones iberoamericanas. Por último, se pretende describir las frecuencias alélicas en los distintos grupos. En el estudio se incluyeron 385 muestras de individuos: 139 mestizos, 197 amerindios y 49 afro-caribeños. Los genotipos CYP2D6 fueron determinados por XL-PCR y PCR tiempo real. Se determinaron las variantes alélicas *2, *3, *4, *5, *6, *10, *17, *29, *35 y *41. Para la población total estudiada las frecuencia de PMs y UMs fueron respectivamente 6% y 6.5%. El porcentaje de individuos UMs fue mayor en la población mestiza que en la amerindia. La frecuencia de UMs varió de 3.6 a 10.1% y la de PMs de 1.4 a 10.1% en los grupos costarricenses. Las frecuencias más altas de UMs (10.1%) y de PMs (10.2%) se encontraron respectivamente en las poblaciones mestiza y amerindia. En conclusión, las frecuencias de UMs y PMs de CYP2D6 varían ampliamente en las poblaciones mestiza, amerindia y afro-caribeña de Costa Rica. Investigaciones futuras en la población de Costa Rica deberían orientarse a identificar nuevas variantes del CYP2D6 mediante métodos de secuenciación, así como a determi- nar el fenotipo de CYP2D6 con el objetivo de establecer la relación fenotipo-genotipo. Finalmente, es necesario realizar estudios adicionales que involucren marcadores genéticos de ancestría en la población costarricense.

Association and treatment response to capecitabine-based chemoradiotherapy with CYP2C9 polymorphism in head and neck cancer.

Aims : The aim of the present study is to investigate the association of polymorphism in cytochrome P450 2C9 (CYP2C9) with head and neck squamous cell carcinoma (HNSCC) and response in patients receiving chemoradiotherapy. Materials and Methods : One hundred ten males suffering from locally advanced head and neck squamous cell carcinoma and an equal number of healthy controls were genotyped for CYP2C9*2 and CYP2C9*3, leading to poor metabolizers (PMs) by PCR-based RFLP. Each case was assessed thoroughly for treatment response following WHO criteria. Results : The frequency of heterozygous genotypes of both CYP2C9*2 (27.3%) and CYP2C9*3 (20.1%) were found to be significantly higher in the HNSCC cases as compared to the healthy controls. Tobacco intake in the form of chewing or smoking and alcohol intake resulted in several fold increase in the risk to HNSCC in the cases carrying variant genotypes of CYP2C9*2 or CYP2C9*3. Further, majority of the cases assessed for response (134) carrying variant alleles of both CYP2C9*2 (65.3%) or CYP2C9*3 (70.58%) were found to respond poorly to the radio-chemotherapy. Conclusions : The data suggests a significant association of the CYP2C9 polymorphism with HNSCC and treatment outcome underlining the importance of pretherapeutic genotyping in determining the treatment schedule.