Distribution of polymorphisms in the CYP2C9 gene and CYP2C19/CYP2C9 haplotypes among Venezuelan populations.

BACKGROUND: Polymorphisms with decreased enzyme activity of their gene products have been reported in region CYP2C with population variations in haplotype structure. AIM: To estimate the allelic and genotypic frequencies of variants CYP2C9*2 and CYP2C9*3 and of CYP2C9/CYP2C19 haplotypes in Venezuelan populations. SUBJECTS AND METHODS: Six hundred and thirty-four individuals from nine admixed populations (AP) and the Warao indigenous group were studied. Allelic frequencies, linkage disequilibrium and genetic distances for haplotypes were calculated and compared within Venezuela and with data available in the literature. RESULTS: Heterogeneity in the distribution of CYP2C9 alleles and CYP2C9/CYP2C19 haplotypes among the AP and the Warao was observed. The joint frequency of haplotypes, with at least one non-functional variant, shows values in AP between 21-41%, while in Warao it reaches 5%. The haplotype that includes the Asian and rare Latin America CYP2C19*3 allele was detected in most AP and in Warao. Pairwise Fst values showed that the Warao was an outlier compared with the AP, while these are closer to European-derived populations. No significant correlation was found between haplotype frequencies and admixture. CONCLUSIONS: These results support the need to understand the distribution of genomic biomarkers related to the metabolism of drugs, for planning national public health strategies.

Distribution of CYP2C19*2 and CYP2C19*3 polymorphisms in Venezuelan populations with different admixture.

BACKGROUND: The conquest and colonization of Venezuela generated very heterogeneous populations as a product of admixture; for this reason, the distribution of polymorphisms of the CYP2C19 gene was studied in various Venezuelan populations. METHODS: Two hundred and eighty-one individuals, from three Venezuelan populations with different admixtures, were genotyped for CYP2C19*2 and CYP2C19*3 polymorphisms. Differences between groups were analysed using a chi-square test of heterogeneity and association of allele frequencies with the level of genetic admixture was performed using a principal component analysis (PCA). No significant differences in distribution of alleles, genotypes and phenotypes were found between the populations studied. RESULTS: In Venezuela, high frequencies of the alleles CYP2C19*2 and CYP2C19*3 were found compared with Europeans, Africans and Latin Americans, similar to those reported in Asia. PCA analysis suggested that the presence of alleles CYP2C19*2 and CYP2C19*3 is associated with the indigenous component in the Venezuelan populations studied. CONCLUSIONS: Future studies are needed to confirm this association. High frequencies of intermediate metabolizers (20-38%) and of poor metabolizers (2-7%) were observed, similar to values reported for Asians and higher than those reported for South Americans. This is the first study evaluating CYP2C19 polymorphisms in the Venezuelan general population.

Perception of the usefulness of drug/gene pairs and barriers for pharmacogenomics in Latin America.

Pharmacogenetics and Pharmacogenomics areas are currently emerging fields focused to manage pharmacotherapy that may prevent undertreatment while avoiding associated drug toxicity in patients. Large international differences in the awareness and in the use of pharmacogenomic testing are presumed, but not well assessed to date. In the present study we review the awareness of Latin American scientific community about pharmacogenomic testing and the perceived barriers for their clinical application. In order to that, we have compiled information from 9 countries of the region using a structured survey which is compared with surveys previously performed in USA and Spain. The most relevant group of barriers was related to the need for clear guidelines for the use of pharmacogenomics in clinical practice, followed by insufficient awareness about pharmacogenomics among clinicians and the absence of regulatory institutions that facilitate the use of pharmacogenetic tests. The higher ranked pairs were TPMT/thioguanine, TPMT/azathioprine, CYP2C9/warfarin, UGT1A1/irinotecan, CYP2D6/amitriptiline, CYP2C19/citalopram and CYP2D6/clozapine. The lower ranked pairs were SLCO1B1/simvastatin, CYP2D6/metoprolol and GP6D/chloroquine. Compared with USA and Spanish surveys, 25 pairs were of lower importance for Latin American respondents. Only CYP2C19/esomeprazole, CYP2C19/omeprazole, CYP2C19/celecoxib and G6PD/dapsone were ranked higher or similarly to the USA and Spanish surveys. Integration of pharmacogenomics in clinical practice needs training of healthcare professionals and citizens, but in addition legal and regulatory guidelines and safeguards will be needed. We propose that the approach offered by pharmacogenomics should be incorporated into the decision-making plans in Latin America.

Activity and levels of factor XIII in a Venezuelan admixed population: association with rs5985 (Val35Leu) and STR F13A01 polymorphisms.

INTRODUCTION: The single nucleotide polymorphism Val35Leu has been described within the A subunit of gene Factor XIII (FXIII-A) in association with an increase of FXIII activity. In the gene's promoter region STR F13A01 is present, however there is no available data related about its influence on the expression of FXIII. MATERIALS AND METHODS: Blood samples were obtained from apparently healthy and unrelated biologically individuals from northeastern area of Venezuela. The system Val35Leu was amplified by PCR-RFLP using MseI as restriction enzyme. FXIIIA and FXIIIB levels were measured by rocket- immunoelectrophoresis. FXIII activity was measured with a Berichrom kit and fibrinogen by clot weigh method. RESULTS: FXIII-A had an activity range between 50-184% and FXIII-B between 50-155%. FXIII activity had a range of 59-147%. Fibrinogen was found between 122-502 mg/dL. None of these values showed association with Val35Leu genotypes. In the third fibrinogen tertile a higher FXIII activity was found (96 ± 24%) and a higher frequency of Leu/Leu genotype (7.02%). A significant correlation between fibrinogen and FXIII activity (r = 0.2706, p > 0.01) was observed. Nine different alleles were detected in the STR polymorphism, with the most frequent alleles being 7 (24.70%), 6 (15.06%), 5 (22.29%), 4 (18.07%), and 3.2 (13.25). The results suggest an increase in FXIII activity as the number of repetitions in F13A01 increased up to allele 5. CONCLUSIONS: This study offers new genetic information of FXIII activity and levels reference values from Venezuelan human population.

Natural selection and molecular evolution in primate PAX9 gene, a major determinant of tooth development.

Large differences in relation to dental size, number, and morphology among and within modern human populations and between modern humans and other primate species have been observed. Molecular studies have demonstrated that tooth development is under strict genetic control, but, the genetic basis of primate tooth variation remains unknown. The PAX9 gene, which codes for a paired domain-containing transcription factor that plays an essential role in the development of mammal dentition, has been associated with selective tooth agenesis in humans and mice, which mainly involves the posterior teeth. To determine whether this gene is polymorphic in humans, we sequenced approximately 2.1 kb of the entire four-exon region (exons 1, 2, 3 and 4; 1,026 bp) and exon-intron (1.1 kb) boundaries of 86 individuals sampled from Asian, European, and Native American populations. We provided evidence that human PAX9 polymorphisms are limited to exon 3 only and furnished details about the distribution of a mutation there in 350 Polish subjects. To investigate the pattern of selective pressure on exon 3, we sequenced ortholog regions of this exon in four species of New World monkeys and one gorilla. In addition, orthologous sequences of PAX9 available in public databases were also analyzed. Although several differences were identified between humans and other species, our findings support the view that strong purifying selection is acting on PAX9. New World and Old World primate lineages may, however, have different degrees of restriction for changes in this DNA region.

Beta-globin gene cluster haplotypes as evidence of African gene flow to the northeastern coast of Venezuela.

In order to study the origin of mutation HBB*S in Sucre and Anzoátegui states and the genetic affinities of these Venezuelan populations with other human groups, the beta-globin gene cluster haplotypes were determined for 28 sickle cell and/or S-beta thalassemia patients and for 37 individuals with normal hematological parameters. Bantu, Benin, Senegal, and atypical haplotypes were identified in 50%, 36%, 2%, and 12% of the HBB*S chromosomes, respectively. Similar results have been published for Venezuelan patients from the central states, but a different trend is shown in a publication based on a group of patients from different regions of the country. For HBB*A, haplotype 2 (+ - - - -), characteristic of non-African groups, was the most common (39%), followed by haplotype 3 (- - - - +) of African origin, and haplotype 6 (- + + - +), also typical of non-Africans. The results reveal a high level of admixture of the Sucre-Anzoátegui population. The importance of specific conditions which have acted differently in the Venezuelan populations, such as founder effect, genetic drift, isolation, and endogamy are discussed. Genetic distances between the Sucre-Anzoátegui sample and several other human populations calculated on the basis of the HBB*S and HBB*A haplotypes revealed similar results, the closest genetic relationships being observed in relation to Bantu-speaking groups. These results confirm the utility of the beta-globin haplotypes for population studies and contribute to knowledge of the Venezuelan gene pool.

Y-chromosome evidence for differing ancient demographic histories in the Americas.

To scrutinize the male ancestry of extant Native American populations, we examined eight biallelic and six microsatellite polymorphisms from the nonrecombining portion of the Y chromosome, in 438 individuals from 24 Native American populations (1 Na Dené and 23 South Amerinds) and in 404 Mongolians. One of the biallelic markers typed is a recently identified mutation (M242) characterizing a novel founder Native American haplogroup. The distribution, relatedness, and diversity of Y lineages in Native Americans indicate a differentiated male ancestry for populations from North and South America, strongly supporting a diverse demographic history for populations from these areas. These data are consistent with the occurrence of two major male migrations from southern/central Siberia to the Americas (with the second migration being restricted to North America) and a shared ancestry in central Asia for some of the initial migrants to Europe and the Americas. The microsatellite diversity and distribution of a Y lineage specific to South America (Q-M19) indicates that certain Amerind populations have been isolated since the initial colonization of the region, suggesting an early onset for tribalization of Native Americans. Age estimates based on Y-chromosome microsatellite diversity place the initial settlement of the American continent at approximately 14,000 years ago, in relative agreement with the age of well-established archaeological evidence.

Diversidad mitooondrial en el nor-occidente de enezuela. implicaciones para prrobables rutas migratorias prehispániass / Mitochondrial diversity in Northwest Venezuela. Implications for probable prehispanic migratory routes.

La utilidad del ADN mitocondrial (ADNmt) para determinar afinidad genética entre grupos indígenas contemporáneos e inferir sobre migraciones, ha sido demostrada; pero la imposibilidad de estudiar grupos prehispánicos extintos, limita las inferencias sobre migraciones en esa época. El mestizaje en poblaciones neoamericanas ha sido caracterizado por uniones entre hombres europeos y mujeres indígenas, permitiendo detectar en la población contemporánea haplogrupos mitocondriales amerindios que informan sobre poblaciones extintas. Para conocer los linajes femeninos en el occidente de Venezuela, se estudiaron los haplogrupos del ADNmt a partir de RFLP, en una muestra de 193 individuos con antepasados procedentes del occidente de Venezuela, 81 del Estado Lara (Barquisimeto) y 112 de tres pueblos del Estado Falcón (Macu-quita=25, Macanillas=29 y Churuguara=58). Se comparó la distribución de haplogrupos entre las poblaciones y se estimó el mestizaje por línea femenina en ellas. Se comparó la distribución de cuatro haplogrupos indígenas con otras regiones de América. Se observa que en las cuatro poblaciones predominan haplogrupos amerindios, seguidos de los africanos. Al comparar la fracción indígena con el resto de América encontramos que Macanillas, Lara y Churuguara se asemejan a grupos de Amazonas y Suramérica, mientras que Macuquita a Aruba. Esto sugiere una diversidad genética importante en esa zona como probable ruta de paso hacia el sur y el Caribe; además refleja vínculos genéticos importantes entre grupos prehispánicos de Aruba y los de la Península de Paraguaná. Evidencias arqueológicas soportan estos postulados. Se recomienda aumentar la muestra y realizar análisis de secuencias para un nivel mayor de precisión.

Mitocondrial DNA (mtDNA) has been widely used to study genetic relationships between contemporary Amerindian groups and to infer ancestral migration movements; however inferences about migration routes of prehispanic extinct groups are difficult. Admixture of Neoamerican groups has been characterized by unions between European males and Amerindian females. This allows the identification in present populations of Amerindian mitocondrial haplogroups which give information on ancestral groups. In order to investigate female lineages present in western Venezuela, RFLP haplogroups from mtDNA were obtained from 193 individuals with grandparents from this region, 81 from the State of Lara (Barquisimeto) and 112 from 3 towns of the State of Falcon (Macuquita=25; Macanilla=29 and Churuguara=58). Comparison of haplogroup distributions between groups was performed, and admixture estimates based on female lineages were obtained. The distribution of four Amerindian haplogroups was compared with those of other populations from the American Continent. In our four samples Amerindian haplogroups predominate, followed by those of African origin. In the comparison of the mtDNA Amerindian fraction with other populations we find that Macanillas, Lara and Churuguara are similar to South American and Amazonian groups whilst Macuquita is similar to groups from Aruba. Our findings suggest an important genetic diversity in this region, explained by migration routes to and from the south and the Caribean. They also suggest genetic relationship between prehispanic groups from Aruba and those from the Paraguaná peninsula, which have been inferred by archeological evidences. An increase in sample size and analysis of sequences for more precision is recommended.

Un análisis multivariante del locus dys19: estudio comparativo en ocho poblaciones venezolanas / A multivariate analysis of locus Dys19: comparative study in eight Venezuelan populations

Se analizaron las frecuencias alélicas del locus DYS19 provenientes de 5 poblaciones rurales venezolanas deascendencia africana (Panaquire; Sotillo; Curiepe; Birongo; Ganga), y se compararon con otras 3 de ascendencia canaria (San Antonio; San Diego; Hoyo de la Cumbre) y con otras reportadas a nivel mundial, utilizando técnicas multivariantes como el Análisis de Correspondencias Binarias (ACB) y la Clasificación Automática. Se pudieron definir 4 grupos de poblaciones asociados a alelos específicos y diferentes orígenes geográficos. Todas las poblaciones venezolanas se ubicaron en el grupo europeo, lo que indica un flujo génico europeo importante por vía masculina en ellas; no obstante, el uso del ACB y la Clasificación Automática permitió diferenciar en un subgrupo a las 5 poblaciones rurales de ascendencia africana. Los resultados obtenidos reflejan la utilidad de los métodos multivariantes utilizados para maximizar el poder discriminante de loci altamente informativos como el DYS19, cuando no se dispone de recursos para estudiar varios loci simultáneamente. Además ofrecieron la posibilidad de mejorar la calidad de la información genética que se poseía sobre las poblaciones venezolanas estudiadas.

The allelic frequencies of locus DYS19 from 5 rural African-derived Venezuelan populations (Panaquire; Sotillo; Curiepe; Birongo; Ganga) were analyzed, and compared with 3 Canarian-derived Venezuelan populations (San Antonio; San Diego; Hoyo de la Cumbre) and with others reported to worldwide, using multivariate method like Correspondences Analysis and Cluster Analysis. Four population clusters were found to be associated with specific alleles and different geographic origins. All the Venezuelan populations were localized in the European cluster, which indicates the existence in them of an important European gene flow through male. Nevertheless the use of both Correspondences Analysis and Cluster Analysis simultaneously, allowed to differentiate in a sub cluster with the 5 rural African-derived Venezuelan populations. The results show the usefulness of the multivariate statistical methods to maximize the discrimination power of highly informative loci like DYS19, when resources are not available to study many loci simultaneously. Furthermore its use improved the quality of the genetic information which already existed for some of the Venezuelan populations studied.

Ribeiro's typology, genomes, and Spanish colonialism, as viewed from Gran Canaria and Colombia

Four biallelic and six multiallelic Y-chromosome polymorphisms were investigated in 59 Gran Canarian, 60 North African Berber and 46 Spanish subjects. These new data were merged with equivalent literature information to obtain the parental Y-chrosomomal contribution in Gran Canarians, Colombians, and Venezuelans. The results were then compared, for Gran Canarians and Colombians, to those derived from autosomal and mtDNA. In both groups, the Spanish Y-chromosome contribution was much more marked than that estimated using mtDNA. This analysis showed a usual trend in the Spanish Colonial history, characterized by a demographic collapse of the aboriginal population, but with considerable introgression of genes through native women. In accordance to D. Ribeiro's typology for peoples subjected to Colonialism, the Y-chromosomes of these admixed populations are classified as transplanted, their mtDNA as witness, and their autosome sets as new.