Relevance of the ancestry for the variability of the Drug-Metabolizing Enzymes CYP2C9, CYP2C19 and CYP2D6 polymorphisms in a multiethnic Costa Rican population

Abstract

CYP2C9, CYP2C19 and CYP2D6 metabolize around 40% of drugs and their genes vary across populations. The Costa Rican population has a trihybrid ancestry and its key geographic location turns it into a suitable scenario to evaluate interethnic differences across populations. This study aims to describe the diversity of CYP2C9, CYP2C19 and CYP2D6 polymorphisms in Costa Rican populations in the context of their ancestry. A total of 448 healthy individuals were included in the study: Bribri (n= 47), Cabécar (n= 27), Maleku (n= 16), Guaymí (n= 30), Huetar (n= 48), Chorotega (n= 41), Admixed/Mestizos from the Central Valley/Guanacaste (n= 189), and Afro-Caribbeans (n= 50) from Limón. CYP2C9 (alleles *2, *3, *6) and CYP2C19 (*2, *3, *4, *5, *17) genotypes were determined by Real-Time PCR. African, European and Native American ancestry were inferred using 87 ancestry informative markers. The frequency of the decreased activity allele CYP2C9*2 is lower in the self-reported Amerindian groups compared to the admixed population, and the highest frequencies of CYP2C19*2 (null activity) and the CYP2C19*17 (increased activity) were found in the self-reported Afro-Caribbean population. Moreover, a frequency of 0.7 % CYP2C9 gPMs in the Admixed population and a variable frequency of CYP2C19 gUMs (0.0-32.6 %, more prevalent in Afro-Caribbeans) in Costa Rican populations, was found. Finally, the following alleles were positively correlated with genomic African ancestry and negatively correlated with genomic Native American ancestry: CYP2D6*5 (null activity), CYP2D6*17 (decreased activity), CYP2D6*29 (decreased activity) and CYP2C19*17 (increased activity). No correlation for CYP2C9 polymorphisms and genomic ancestry was found. Further studies assessing the CYP2C9 and CYP2C19 sequence in these populations, preferentially by sequencing these genes, are warranted.

PharmVar GeneFocus: CYP2C19

“…In addition, the frequency of genetic variants as well as their distribution and combination within a haplotype may differ in admixed populations when compared with parental populations. For example, CYP2C19 has a higher number of rare genetic variants in Hispanics (4%), a highly admixed population, when compared with Europeans (0.05%), and CYP2C19*2 and *17 were found at a higher frequency in self‐reported Afro‐Caribbean subjects from Costa Rico than mestizos of the same country 72,73 . In addition, frequencies may also profoundly differ among indigenous populations, including those in North, South, and Central America 74–76 …”

“…For example, CYP2C19 has a higher number of rare genetic variants in Hispanics (4%), a highly admixed population, when compared with Europeans (0.05%), and CYP2C19*2 and *17 were found at a higher frequency in self-reported Afro-Caribbean subjects from Costa Rico than mestizos of the same country. 72,73 In addition, frequencies may also profoundly differ among indigenous populations, including those in North, South, and Central America. [74][75][76] Considering CYP2C19*1 through *35 (excluding the CYP2C19*36 and *37 deletion alleles), hundreds of allele REVIEW combinations are possible, and thus, the number of genotypes in a population or patient cohort can be quite large.…”

Genomic Ancestry,CYP2D6,CYP2C9, andCYP2C19Among Latin Americans

“…The high percentages of the nullactivity alleles *4 and *5 in Bribri account for its highest percentage of CYP2D6 gPMs in our Ibero-American dataset (21.7%). 17 Importantly, although the *4 allele is common and cosmopolitan, allele *5 is rarer worldwide. Our studied populations with > 90% of Native American ancestry host 31 copies of the CYP2D6*5 allele, whereas given its low frequency in Europeans (~2%) we would expect only 2.4 copies if all these alleles would have been the product of European introgression.…”

CYP2D6 and CYP2C19 genotyping in psychiatry

“…A study in 1827 patients showed that over 90% reported at least one drug-induced side effect and high levels of distress (1). When patients suffer from one movement disorder, the chances of developing a second or third movement disorder are increased (71). These side effects impair their psychosocial functioning and quality of life (1).…”