Martha Sosa-Macías

CYP2D6 genotype and phenotype in Amerindians of Tepehuano origin and Mestizos of Durango, Mexico.

Although the drug‐metabolizing enzyme CYP2D6 has been studied extensively in subjects of differing ethnicities, limited CYP2D6 pharmacogenetic data are available for the Amerindian population and Mestizos of Mexico. Dextromethorphan hydroxylation phenotype was studied in Tepehuano Amerindian (n = 58) and Mestizo (n = 88) subjects, and 195 individuals (85 Tepehuano Amerindians and 110 Mestizos) were genotyped by polymerase chain reaction‐restriction fragment length polymorphism methods to identify the frequencies of the CYP2D6*3, *4, *6, and *10 alleles. Tepehuano Amerindian subjects lacked the poor metabolizer (PM) phenotype, whereas in Mestizos the PM phenotype frequency was 6.8%. The CYP2D6*3, *6, and *10 alleles were not found in Tepehuano Amerindians. The CYP2D6*4 allele had a low frequency (0.006) in this Amerindian group. In the Mestizo group, the CYP2D6*3, *4, and *10 alleles had frequencies of 0.009, 0.131, and 0.023, respectively. The CYP2D6*6 allele was not found in Mestizos. The genotype‐phenotype association was strongly statistically significant (r2 = .45; P = .005) in Mestizos. The Tepehuano population was found to have a low phenotypic and genotypic CYP2D6 diversity and differed from other Amerindian groups. On the other hand, the frequencies of the CYP2D6 variant alleles in Mestizos were similar to those reported for whites.

Distribution of CYP2D6 and CYP2C19 polymorphisms associated with poor metabolizer phenotype in five Amerindian groups and western Mestizos from Mexico.

BACKGROUND The distribution of polymorphisms in the CYP2D6 and CYP2C19 genes allows inferring the potential risk for specific adverse drug reactions and lack of therapeutic effects in humans. This variability shows differences among human populations. The aim of this study was to analyze single-nucleotide polymorphisms related to a poor metabolizer (PM) phenotype in nonpreviously studied Amerindian groups and Mestizos (general admixed population) from Mexico. METHODS We detected by SNaPshot(®) different polymorphisms located in CYP2D6 (*3, *4, *6, *7, and *8) and CYP2C19 (*2, *3, *4 and *5) in western Mestizos (n=145) and five Amerindian groups from Mexico: Tarahumaras from the North (n=88); Purépechas from the Center (n=101); and Tojolabales (n=68), Tzotziles (n=88), and Tzeltales (n=20) from the Southeast. Genotypes were observed by capillary electrophoresis. The genetic relationships among these populations were estimated based on these genes. RESULTS AND DISCUSSION The wild-type allele (*1) of both genes was predominant in the Mexican populations studied. The most widely observed alleles were CYP2C19*2 (range, 0%-31%) and CYP2D6*4 (range, 1.2%-7.3%), whereas CYP2D6*3 was exclusively detected in Mestizos. Conversely, CYP2C19*4 and *5, as well as CYP2D6*3, *6, *7, and *8, were not observed in the majority of the Mexican populations. The Tarahumaras presented a high frequency of the allele CYP2C19*2 (31%) and of homozygotes *2/*2 (10.7%), which represent a high frequency of potentially PM phenotypes in this Amerindian group. The genetic distances showed high differentiation of Tarahumaras (principally for CYP2C19 gene). In general, a relative proximity was observed between most of the Amerindian, Mexican-Mestizo, and Latin-American populations. CONCLUSION In general, the wild-type allele (*1) predominates in Mexican populations, outlining a relatively homogeneous distribution for CYP2C19 and CYP2D6. The exception is the Tarahumara group that displays a potentially increased risk for adverse reactions to CYP2C19-metabolized drugs.

Influence of CYP2D6 Deletion, Multiplication,-1584C~G, 31G~A and 2988G~A Gene Polymorphisms on Dextromethorphan Metabolism among Mexican Tepehuanos and Mestizos

The aim of this study was to explain the variability of CYP2D6 activity by the identification of CYP2D6 deletion and multiplications, and the single-nucleotide polymorphisms (SNPs) –1584C→G, 31G→A and 2988G→A in Mexican Mestizo and Tepehuano subjects. One hundred twelve Mestizos and 99 Tepehuano Amerindians were studied, who were previously phenotyped with dextromethorphan. The frequencies of CYP2D6*2A [–1584C→G] and *35 [–1584C→G, 31G→A] were 10.7 and 4.1%, respectively, in Mestizos, which is evidently a trend towards an extensive metabolism in carriers of the –1584G change. In Tepehuanos, *2A was identified with a frequency of 20%, and the allele *35 was not found. The frequencies of CYP2D6*5 (deletion) and *41[2988G→A] were 1.3 and 2.2% in Mestizos and 0.5 and 1% in Tepehuanos, respectively. The SNP 2988A was found to be significantly related with the intermediate metabolizer phenotype in Mestizos (R = 0.309; n = 88; p = 0.006). The multiplications had frequencies of 4.1% in Mestizos and 1.5% in Tepehuanos. Only in the Mestizos did the presence of multiplications significantly decrease the DM/DX (dextromethorphan/dextrorphan) values (R = 0.273; n = 88; p = 0.016). The polymorphisms studied had different frequencies between Tepehuanos and Mestizos (p < 0.001); however, in the Tepehuano group these had a low influence on their phenotypic expression. It helps to understand the genotype-phenotype relationships of CYP2D6 in our studied populations.

CYP2D6 gene polymorphisms and predicted phenotypes in eight indigenous groups from northwestern Mexico

AIM Polymorphisms in CYP2D6 impact the interindividual and interethnic variability of drug efficiency; therefore, we determined the CYP2D6 allele distribution in eight Amerindian groups from northwestern Mexico and compared them with the frequencies in Mexican Mestizos. MATERIALS & METHODS A total of 508 Amerindians were studied. Genotyping of CYP2D6*5 and multiplication alleles was performed by long-range PCR, while CYP2D6*2, *3, *4, *6, *10, *17, *29, *35, *41 and copy number were evaluated by real-time PCR. RESULTS The most frequent alleles were CYP2D6*2 (0.05-0.28), CYP2D6*4 (0.003-0.21) and multiplications (0.043-0.107). CYP2D6*5, *6, * 10 and *41 were not observed in the majority of Amerindians, and CYP2D6*3, *17, *35 and *29 were not detected. The poor metabolizer genotype ( *4/*5) was lower (0.2%) in Amerindians than in Mestizos (5%); conversely, the ultrarapid metabolizer genotype was higher (12.6%) in indigenous groups than in Mestizos (7%). CONCLUSION Our data show a lower frequency of CYP2D6 inactive alleles and a higher frequency of duplication/multiplication of CYP2D6 active alleles in indigenous populations that in Mestizos. Original submitted 14 August 2013; Revision submitted 7 October 2013.

Influence of admixture components on CYP2C9*2 allele frequency in eight indigenous populations from Northwest Mexico

We previously documented the lowest frequency of CYP2C9*2 in Mexican indigenous Tepehuanos followed by Mestizos and Mexican-Americans populations, suggesting a negative correlation between the CYP2C9*2 frequency and the degree of Asian ancestry in indigenous Americans. We determined the influence of ethnic admixture components on the CYP2C9 allele distribution in 505 Amerindian from eight indigenous populations through genotyping CYP2C9*2, *3 and *6 alleles by real-time PCR and molecular evaluation of ancestry. The frequencies for CYP2C9*2 were 0.026 in Seris and 0.057 in Mayos, being higher than in Asians (P<0.001). CYP2C9*3 was found in Tarahumaras (0.104), Mayos (0.091), Tepehuanos (0.075), Guarijíos (0.067), Huicholes (0.033) and Coras (0.037), with East Asians having lower frequencies than the former three groups (P<0.001). CYP2C9*6 was not found. The frequency of CYP2C9*2 was lower in Amerindians than in European populations, and higher than their Asian ancestors. The presence of this allele in ethnic groups in Mexico can be explained by European admixture.

Cytochrome P450 genetic polymorphisms of Mexican indigenous populations.

Abstract This review focuses on the genetic polymorphisms of the cytochrome P450 (CYP) genes in Mexican indigenous populations, who are a part of the wide ethnic diversity of this country. These native groups have a particular historical trajectory that is different from the Mexican Mestizos. This variability may be reflected in the frequency distribution of polymorphisms in the CYP genes that encode enzymes involved in the metabolism of drugs and other xenobiotics. Therefore, these polymorphisms may affect drug efficacy and safety in indigenous populations in Mexico. The present study aimed to analyze the prevalence of CYP polymorphisms in indigenous Mexicans and to compare the results with studies in Mexican Mestizos. Because the extrapolation of pharmacogenetic data from Mestizos is not applicable to the majority of indigenous groups, pharmacogenetic studies directed at indigenous populations need to be developed. The Amerindians analyzed in this study showed a low phenotypic (CYP2D6) and genotypic (CYP2D6, CYP2C9) diversity, unlike Mexican Mestizos. The frequency of polymorphisms in the CYP1A1, CYP2C19, CYP2E1, and CYP3A4 genes was more similar among the Amerindians and Mexican Mestizos, with the exception of the CYP1A2 gene, whose *1F variant frequency in Mexican Amerindians was the highest described to date.

A Comparative Study of CYP3A4 Polymorphisms in Mexican Amerindian and Mestizo Populations

Cytochrome P-450 3A4 (CYP3A4) contributes to the metabolism of approximately half the drugs in clinical use today. The aim of the present study was to determine the frequency of the CYP3A4*1B, *2, *4, *5, and *18 alleles amongst both Tepehuan Amerindians, a native group that has inhabited northern Mexico for thousands of years, and Mestizo Mexicans, and to compare the data with those of other populations. Genotyping experiments revealed that 8.8 and 8.0% of the Mestizo and Tepehuano subjects, respectively, carried the CYP3A4*1B allele. Only one Mestizo subject was heterozygous for the CYP3A4*2 variant, while CYP3A4*4, *5 and *18 allelic variants were not detected in either group. On the other hand, the frequencies of the CYP3A4*1B variant in Mestizos and Tepehuanos were similar to those reported for Caucasians, but different from those observed for African and Asian populations.

Importance of the geographic barriers to promote gene drift and avoid pre‐ and post‐Columbian gene flow in Mexican native groups: Evidence from forensic STR Loci

OBJECTIVE To analyze the origin, structure, relationships, and recent admixture in Mexican Native groups based on 15 STRs commonly used in human identification. METHODS We analyzed 39 Mexican Native population samples using STR databases based on the AmpFlSTR® Identifiler kit (n = 3,135), including Mexican-Mestizos (admixed), European and African populations, as reference. RESULTS Based upon effective population size (Ne) differences, Native groups were clustered into three regions: i) Center-Southeast groups, characterized by larger Ne, migration rate (Nm), genetic diversity (He), and relative homogeneity principally in the Yucatan Peninsula; ii) Isolated southern groups from Chiapas and Oaxaca, characterized by lower Ne, Nm, and He (i.e. higher isolation and genetic differentiation); iii) North-Northwest groups, which are similar to the previous group but are characterized by generating the widest gene flow barrier in the Pre-Hispanic Mexican territory, and currently by elevated admixture in some northern Native groups. Despite the relative congruence between genetic relationships with cultural, linguistic, geographic criteria, these factors do not explain the present-day population structure of Native groups, excepting in those linguistically related to the Mayan that show higher homogeneity. The Isolation by distance model was demonstrated at long distances (>1,500 km), whereas geographic isolation stands as a determining factor to avoid both non-indigenous admixture and bottleneck processes. CONCLUSIONS Different dynamics of gene flow and drift were observed among Mexican Native groups, highlighting the geographic barriers (mountains, canyons and jungle regions) as the main factor differentiating Pre-Hispanic populations, and eventually helping to avoid Post-European contact admixture and population bottleneck. Am J Phys Anthropol 160:298-316, 2016.

Forensic parameters for 15 STRs in eight Amerindian populations from the north and west of Mexico

Allele frequency distributions for 15 STR loci (AmpFlSTR Identifiler kit) were estimated in 825 volunteers of the following eight Mexican-Amerindian populations from two geographical regions: (1) North: Tarahumara (204), Mayo (45), Seri (28), and Guarijío (17); (2) Northwest: Tepehuano (123), Mexicanero (84), Cora (85), and Huichol (239). Genotype frequency distribution was in agreement with Hardy-Weinberg expectations for all 15 STRs, excepting for two loci (D13S317 and FGA) in the Huichol population. The power of discrimination and power of exclusion values were both larger than 0.99999. These STR databases will support the correct interpreting of DNA profiles in paternity testing and forensic cases in Mexican-Amerindian groups from these regions, until know poorly studied. Genetic distances and pairwise comparisons were estimated between populations. A significant genetic differentiation was observed between these Mexican-Amerindian groups (F(ST)=3.43%; p=0.0000) that was 10 times larger than the observed between Mestizos (F(ST)=0.34%), which represent most of the Mexican population (~90%). This result was in agreement with the incapability to cluster these Native American populations by geographic criteria. Pre-Colombian descriptions of Aridoamerica, including the North region of Mexico, suggest genetic drift effects to explain this noticeable population differentiation of Mexican-Amerindian groups.

Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children

Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11–5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62–78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42–191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94–31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05–6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19–31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children.