CYP2D6 and CYP2C19 Genes Associated with Tricontinental and Latin American Ancestry of Peruvians

Precision medicine seeks to individualize the dose from the beginning of pharmacological therapy based on the characteristics of each patient, genes involved in the metabolic phenotype, ethnicity or miscegenation, with the purpose to minimize adverse effects and optimize drug efficacy. The objective was to review studies that describe the association of the CYP2D6 and CYP2C19 genes with the tricontinental and Latin American ancestry of Peruvians. A bibliographic search was carried out in PubMed/Medline and SciELO, with various descriptors in Spanish and English. The results of this review confirm that the ethnic origin of Peruvians is tricontinental due to European (mainly Spanish), African and Asian migration, in addition to Latin American migration, being 60.2% mixed, 25.8% Amerindian, 5.9% white, 3.6% African descent, 1.2% Chinese and Japanese descent, and 3.3% unspecified. Studies on CYP2C19*3, CYP2D6*2, *3 and *6 have been reported in Peruvians, and the frequency is similar to that studied in Ecuadorians and Colombians. The CYP2C19*3, CYP2D6*3, and CYP2D6*6 alleles found in Peruvians are common in Europeans, Africans, and Asians; while CYP2D6*4 in Africans and CYP2D6*2 related to Asians. In some studies, the ethnic/gene association has not been demonstrated; while others have shown a significant association, which is why further investigation is warranted. It is concluded that the studies on CYP2D6 and CYP2C19 genes associated with the tricontinental and Latin American ancestry of Peruvians are little, and according to what has been investigated, the CYP2C19*3, CYP2D6*2, *3, *4 and *6 alleles have more related to their ancestry.


INTRODUCTION
Precision medicine seeks to individualize the dose from the start of pharmacological therapy based on the characteristics of each patient, ethnicity, and genotype/phenotype, with the aim of minimizing adverse effects and optimizing drug efficacy [1,2]. The CYP2C19 and CYP2D6 genes are highly polymorphic and express drug-metabolizing enzymes, and have an impact on drug efficacy and safety [3,4]. Gene CYP2D6 is located on chromosome 22q13.1, and consists of nine exons and eight introns with more than 135 alleles [4][5][6][7][8], including single nucleotide polymorphisms (SNPs) [9,10].

CYP2D6, CYP2C19 AND ETHNIC ANCESTRY OF PERUVIANS
Genetic ancestry is the information on the biological descent of an individual, including genetic relationships and historical information on the origin and experience of the remote ancestors of the individual. In the case of Peruvians, different levels of genomic ancestry have been reported in 25 regions of Peru; 83% are of American origin and 17% of European origin, and autochthonous genomic inheritance in Peru is around 80%, which corresponds to a very high prevalence of pre-Columbian genes in the current population [13]. Other studies have shown the ethnic origin of Peruvians, which is tricontinental due to European (mainly Spanish), African and Asian (Chinese and Japanese) migration, to which Latin American migration is added [7,12,14,15], being 60.2% admixed (mixed Amerindian and white), 25.8% Amerindian, 5.9% white, 3.6% African descent, 1.2% Chinese and Japanese descent, and 3.3% unspecified [16]. The population of Lima is predominantly admixed (71%) with tricontinental ancestry (European, African and Asian) [2]; for this type of admixture, pharmacogenetic data from other populations are not applicable, so it is vital to have studies on Peruvians [36]. Table 1 [37][38][39][40] summarizes the ethnic origin of Peruvians according to the geographical regions admixed (Coast and Andes), Shimaa (Cusco, Andes), Aymara (Andes of Moquegua, Puno and Tacna) and Ashaninka (Jungle).
In an investigation carried out by Alvarado et al., the frequencies of the allelic variants CYP2D6*3 and CYP2D6*4 were identified in a sample of the Peruvian admixed population stratified by region, 184 subjects from the coast (Lima, n = 134; Tacna, n = 50) and 50 subjects from the Andes (Junín, n = 50) [12]. Continental ancestry and admixture of Old World (Africa, Asia, and Europe), geographic and ethnic diversity of Native American populations contribute to variation in CYP2D6 [3]. Table 2 describes the studies of CYP2C19 and CYP2D6 genes carried out in Peruvians.
The most relevant studies related to the tricontinental ancestry of Peruvians are described below: Wang et al. studied CYP2C19 polymorphism in two provinces (Uygur and Han) of China. A frequency of 5.5% was found for CYP2C19*2/*2 and 30.4% for CYP2C19*1/*2. The metabolic phenotypes are NM in Han 37.7% and in Uygur 40.6%; IM in Han 45.2% and Uygur 34.0%; PM 15.4% in Han and 6.8% in Uygur [47]. Biswas describes that the allele frequencies of CYP2C19*2, *3 and *17 are different in ethnic groups. Africans (37.2%) and Europeans (35.4%) have a higher risk of presenting subtherapeutic effects or adverse effects, which is why they suggest carrying out pharmacogenomic studies of CYP2C19 and evaluating clinical results [48]. (Fig. 1)   Regarding the frequency of metabolizers, it has been reported that poor metabolizers (PM) for CYP2C19 in Caucasian European populations account for 2-5% [27], 4-7% in black Africans [44], 12-23% in Asians [27], specifically 15-17% in Chinese, 18-23% in Japanese, and 12-16% in Koreans [44]. This suggests that the PM phenotype is an autosomal recessive trait that is inherited [44]. Ultra-rapid metabolizers (UM) for CYP2C19*17 are associated with a high risk of bleeding, such as clopidogrel, due to greater exposure to the active metabolite, which inhibits platelet aggregation [30]. PM for CYP2D6 in Europeans represents between 5-10% [21,22,44], 2-5% in African American population, and 0.2%-1.0% in the Asian population [7,9,21]. The UM percentage for CYP2D6 (at least three functional gene copies) in Caucasians is 10%, 3% in African Americans, and 1% in Hispanics, Chinese, and Japanese [34]. Ingelman-Sundberg and Rodríguez-Antona indicate that PMs for CYP2D6 require 30-50 mg of nortriptyline, and UMs require 500 mg of the drug to achieve the same.
Plasma concentrations. Intermediate metabolizers (IMs) are mainly located in Asia due to the high frequency of CYP2D6*10 [33]. In Amerindian populations from Argentina, Costa Rica, Chile, Mexico, Paraguay, Peru, and the United States, normal metabolizers (NM) for CYP2D6 are the most frequent, followed by IM, PM, and UM in that order [11,22].   (2) Table 3 summarizes the genes, alleles, diplotype, phenotype, and activity score.

CYP2D6, CYP2C19 AND LATIN AMERICAN ASCEND-ANCE OF PERUVIANS
Allele frequencies and phenotypes of CYP2D6 have been extensively studied in all African, European, East Asian, and South Asian populations, with very little in the East African and South Pacific regions [8]. In the Latin American population, it is evident that these studies are still scarce, specifically in Native Americans, despite the importance of pharmacogenetics to individualize pharmacological therapy. Next, a review of the studies carried out in admixed and Amerindian populations is made for the CYP2C19 and Frequencies were in the range of 5.9-19.3% for the CYP2C19*2 allele for all populations studied; CYP2C19*3 was not detected [56]. Céspedes-Garro et al. observed the presence of CYP2C19*2 and CYP2C9*17 (frequency of 2-10.3%) in mestizo and ancestral Costa Rican populations [24]. Hernandez-Suarez et al. reported alleles from the Puerto Rican population with a variable frequency of 14.1% for CYP2C19*17, 13.5% for CYP2C19*2, and 0.3% for CYP2C19*4. When stratifying by geographic region, CYP2C19*2 has been observed with a frequency of 11.7%, 13.6%, and 15% in the central, western, and eastern regions, respectively; CYP2C19*17 was 12.5% in the Central and West and 16% in the East [57]. Flores-Angulo et al. observed in the Aragüeño population of Venezuela a frequency of 4.4% of CYP2D6*4, 0.3% of CYP2D6*6, and 1% of CYP2D6*10 [14]. Flores-Gutierrez et al. found in the ancestral Warao population a frequency of 0.022% of CYP2C19*2 and 0.0% of CYP2C19*3 [58]. De Andres et al. found an overlap in actual enzyme capacity between PM and NM for CYP2D6 (3.14%), and overlap of MU for CYP2C19 (11.48%) and NM for CYP2D6 (2.09%) in Nicaraguan mestizo population [59]. Table 4 describes the relationship of: CYP2C19/CYP2D6 genes of Peruvians with populations of Latin America.

CLINICAL IMPLICATION OF CYP2D6 AND CYP2C19
Association studies between genotypes/plasma level and adverse drug effects are not conclusive; for example, Carlsson et al. reported that CYP2C19*2 and *3 genotypes do not influence plasma levels of citalopram, N-desmethylcitalopram, and N,N-didesmethylcitalopram, detected at steady state. The study also concludes that CYP2D6*3, *4, *6 and *2×2 do not influence the plasma levels of citalopram [69]. Thiem et al. found a correlation between CYP2C19*1 and the N-demethylation (first nortriptyline, then Ndesmethylnotriptyline) and hydroxylation (E-10-hydroxy-Ndesmethylnortriptyline) of amitriptyline [70]. While, Aldrich et al. observed an association between the metabolic phenotypes and their clinical implication of citalopram and escitalopram [71]. Gasso et al. conducted a dose-escalation study of fluoxetine based on metabolic phenotype and found that it influences plasma levels [72]. Bousmann et al. indicate that CYP2C19 poor metabolizers (PM) and CYP2C19 ultrarapid metabolizers (UR) require clinical monitoring [32]. Veldic et al. performed a retrospective analysis of CYP2C19 genes in citalopram-treated patients of Caucasian (89.2%), African American (1.1%), Asian (0.7%), and other origins, indicating an association of poor metabolizers with adverse effects [73]. Findling et al. noted that clearance of paroxetine is related to CYP2D6 [74]. While Cherma et al. found in two children (of four participants) CYP2D6 alleles that predict poor metabolizers [75]. Maggo et al. carried out a case-control study in patients with depression and inhabitants of European origin (70%), Maori (11%), Asian (4%), and unspecified ethnic groups. PM was observed for CYP2D6 (n = 15), CYP2C19 (n = 6), and one individual as PM for CYP2C19 [76]. Llerena et al. have described in Hispanics (excluding Amerindians) PM in a percentage ranging from 0-10%, and UM 0-5.3% [77]. Table 5 summarizes the main studies of genotypes, metabolic phenotype, and their clinical implications.

APPLICATION OF PHARMACOGENOMICS TO PRECISION MEDICINE IN PERU
The results of this review show that studies on CYP2C19 and CYP2D6 genes are scarce in Peruvian subpopulations, as pharmacogene association studies, and according to what has been found in the literature, the allelic variants CYP2C19*3, CYP2D6*2 and CYP2D6*3 have a similar frequency in Asians, while CYP2D6*3 and *4 have a greater relationship with Africans. Regarding Latin American descent, there is a greater similarity between Ecuadorians and Colombians. Therefore, it is necessary to carry out studies with a larger number of samples and in the three geographical regions of Peru in order to associate gene allele frequency with the ethnic origin of Peruvians (tricontinental and Latin American) and its influence on the response to drugs; this, at the same time, will allow to have genetic biomarkers typical of Peruvians, and shorten the distance with the other countries of Latin America, where there is more evidence of these studies. In this sense, the Latin American Network for the Implementation and Validation of Pharmacogenomic Clinical Guidelines (RELIVAF), of which Peru is a member, is promoting pharmacogenomic studies in Latin America, and especially in our country, which will allow for greater scientific evidence of the genes, Peruvian genotypes-phenotypes and their association with various drugs, to implement precision medicine in Peru.   Descriptive study RM y UR para CYP2D6 These genotypes do not influence the plasma levels of citalopram and its two metabolites. [69] Descriptive study CYP2D6 CYP2D6 influences the clearance of paroxetine. [74] Open design study PM: CYP2D6*4/*4 It was observed that it influences the plasmatic level; subsequently, fluvoxamine doses were personalized, being three times lower (75-100 mg) to achieve levels of 58 ng/mL.
As it was a very small sample, this association was not statistically significant. [75] Descriptive study CYP2D6 The fluoxetine/(S)-norfluoxetine ratio was found to be low in UR, and higher in IM and PM. [72] Cases and controls study PM para CYP2D6 PM para CYP2C19 On 7/15 PM CYP2D6 were dose intolerants of escitalopram, citalopram, or sertraline. PM CYP2C19 tolerated escitalopram dose but not fluoxetine (minimally metabolized by CYP2C19).
[76] The limitations of this review are the few pharmacogenetic studies in patients and the Peruvian population in general, limited studies of the association of ethnicity/genes/drugs, and the heterogeneous design of the international studies that do not allow a significant association between ethnicity and pharmacogenes. Notwithstanding the foregoing, this study will form part of the scientific evidence for Peruvian doctors and researchers to carry out pharmacogenomic studies according to their specialty, and in the short term, it will be a routine clinical practice tool.

CONCLUSION
It is concluded that the studies on the CYP2D6 and CYP2C19 genes associated with the tricontinental and Latin American ancestry of Peruvians are little, and according to what has been investigated, the CYP2C19*3, CYP2D6*2, *3, *4 and *6 alleles have a greater relationship with European, African and Asian populations. Association studies between genotypes/plasma level and adverse drug effects are not conclusive, which is why multicenter studies with a larger number of patients are warranted.

CONSENT FOR PUBLICATION
Not applicable.

FUNDING
None.

CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.