CYP2D6 variability in populations from Venezuela

Abstract

CYP2D6 is an important cytochrome P450 enzyme that plays an important role in the metabolism of about 25% of currently prescribed drugs. The presence of polymorphisms in the CYP2D6 gene may modulate enzyme level and activity, thereby affecting individual responses to pharmacological treatments. The most prevalent diseases in the admixed population from Venezuela are cardiovascular and cancer, whereas viral, bacterial and parasitic diseases, particularly malaria, are prevalent in Amerindian populations; in the treatment of these diseases, several drugs that are metabolized by CYP2D6 are used. In this work, we reviewed the data on CYP2D6 variability and predicted metabolizer phenotypes, in healthy volunteers of two admixed and five Amerindian populations from Venezuela. The Venezuelan population is very heterogeneous as a result of the genetic admixture of three major ethnical components: Europeans, Africans and Amerindians. There are noticeable inter-regional and inter-population differences in the process of mixing of this population. Hitherto, there are few published studies in Venezuela on CYP2D6; therefore, it is necessary to increase research in this regard, in particular to develop studies with a larger sample size. There is a considerable amount of work remaining before CYP2D6 is integrated into clinical practice in Venezuela.

Several Plasmodium vivax relapses after correct primaquine treatment in a patient with impaired cytochrome P450 2D6 function

“…The molecular analysis of CYP2D6 gene of the patient of this study showed heterozygosity for allele *4, categorized as a non-functional allele [48,49]. CYP2D6*4 was present in all the Venezuelan populations tested in previous studies [50,51], and it has similar allele frequencies in populations of Spain and other Latin American countries, as a result of the process of conquest [50]. Other SNVs or structural variant were not detected.…”

Genetic Diversity of Drug-Related Genes in Native Americans of the Brazilian Amazon

“…44 Studies have reported that other Native American populations have reduced frequencies of nonfunctional alleles in the CYP2D6 gene. In Venezuela and Mexico, mean frequencies of 3% of the *4 allele were reported, 23,45 while in Costa Rica, the observed mean frequency was 7%. 27 There were exceptions in Native Americans: Bribri, and Cabebar from Costa Rica, Bari from Venezuela, and Seris from Mexico presented high frequencies of the referred allele (31, 27, 42, and 21%, respectively).…”

“…27 There were exceptions in Native Americans: Bribri, and Cabebar from Costa Rica, Bari from Venezuela, and Seris from Mexico presented high frequencies of the referred allele (31, 27, 42, and 21%, respectively). 41,45 The intermediate metabolizer (IM) profile is defined by the presence of genotypes with reduced function alleles (*9 and *29). Data estimated by the 1000 Genomes Project demonstrate low frequencies of these alleles in world populations except for AFR, SAS, and EAS.…”

“…Our results differ from other studies with Native Americans that determined high frequencies of these alleles in Seris (41.2%) and Mayos (22.7%) from Mexico and Bari (35%) from Venezuela. 41,45 Perez-Paramo et al have suggested that differentiated profiles of the null/reduced metabolic activity in the CYP2D6 gene in other indigenous populations of South America are the result of food selection and lifestyle processes that these populations have undergone. 46 Patients with PM and IM profiles have a higher risk of developing adverse reactions to CYP2D6-substrate treatments.…”

“…41 Therefore, the lack of PM and the low frequency of IMs in the Amazonian Native Americans of Brazil may represent a lower risk of toxicity development during these therapeutic schemes. 41,45 The UM profile is determined by the presence of functional allele duplications, increasing the enzyme's mechanism of action on metabolism. In the investigation of Amazonian Native Americans, the UM profile was found exclusively in the KAY population at low frequencies (2%).…”