Pharmacogenomic implications of the differential distribution of CYP3A5 metabolic phenotypes among Latin American populations.

This study shows that the distribution of CYP3A5 alleles (*1, *3, *6 and *7) and genotype-predicted CYP3A5 phenotypes vary significantly across Latin American cohorts (Brazilians and the One Thousand Genomes Admixed American superpopulation), as well as among subcohorts comprising individuals with the highest proportions of Native, European or sub-Saharan African ancestry. Differences in biogeographical ancestry across the study groups are the likely explanation for these results. The differential distribution of CYP3A5 phenotypes has major pharmacogenomic implications, affecting the proportion of individuals carrying high risk CYP3A5 phenotypes for the immunosuppressant tacrolimus and the number of patients that would need to be genotyped to prevent acute rejection in kidney transplant recipients under tacrolimus treatment.

Pharmacogenomic implications of the differential distribution of CYP2C9 metabolic phenotypes among Latin American populations.

The CYP2C9 gene encodes the major drug metabolism enzyme CYP2C9. This gene is highly polymorphic, and no-function (CYP2C9*3) plus decreased function (CYP2C9*2, *5, *8 and *11) star alleles (haplotypes) are commonly used to predict CYP2C9 metabolic phenotypes. This study explores the pharmacogenomic implications of the differential distribution of genotype-predicted CYP2C9 phenotypes across Latin American populations. Data from 1,404 individuals from the South American countries Brazil, Colombia and Peru, from Puerto Rico in the Caribbean and from persons with Mexican ancestry living in North America were analysed. The results showed that the distribution of CYP2C9 alleles and diplotypes, and diplotype-predicted CYP2C9 phenotypes vary significantly across the distinct country cohorts, as well as among self-identified White, Brown and Black Brazilians. Differences in average proportions of biogeographical ancestry across the study groups, especially Native American and African ancestry, are the likely explanation for these results. The differential distribution of genotype-predicted CYP2C9 phenotypes has potentially clinically-relevant pharmacogenomic implications, through its influence on the proportion of individuals at high risk for adverse response to medications that are CYP2C9 substrates, the proportion on individuals with CPIC therapeutic recommendations for dosing and choice of nonsteroidal antinflammatory drugs (NSAIDs) and the number of individuals that need to be genotyped in order to prevent adverse effects of NSAIDs. Collectively, these findings are likely to impact the perceived benefits, cost-effectiveness and clinical adoption of pharmacogenomic screening for drugs that are predominantly metabolized by CYP2C9.

Pharmacogenetic differentiation across Latin America.

Aim: To explore the pharmacogenetic differentiation across Latin American populations, using the fixation index statistics (FST). Materials & methods: FST analyses were applied to 1519 pharmacogenetic markers in the 1000 Genomes admixed American superpopulation (1KG_AMR) and an admixed Brazilian sample. Results: Allele-specific FST values for the overall cohort point to little overall pharmacogenetic differentiation (average FST = 0.017); however, moderate differentiation (FST = 0.05-0.15) was observed for 83 markers, while large differentiation (FST = 0.15-0.25) was restricted to three markers. Pairwise FST analysis identified three markers with very large differentiation (FST >0.25). Conclusion: The present study verifies and extends previous reports of little overall pharmacogenetic divergence across Latin America, although a number of markers display substantial differentiation.

African biogeographical ancestry, atopic and non-atopic asthma and atopy: A study in Latin American children.

BACKGROUND: Genetic variants underlying African ancestry have been suggested be implicated in the ethnic-racial inequalities reported for asthma and allergies. OBJECTIVES: To investigate the association between individual African ancestry and asthma symptoms, atopic and non-atopic asthma, and atopy in children. METHODS: A cross-sectional study encompassing 1190 individuals was conducted. African biogeographic ancestry was estimated using 370 539 genome-wide SNPs. Serum levels of specific IgE were measured, and skin prick test (SPT) performed for the most common local aeroallergens. Information on asthma symptoms was obtained by applying the International Study of Allergy and Asthma in Childhood questionnaire. The associations between the proportion of individual African ancestry and the outcomes investigated were analyzed through multivariate models adjusted for socio-environmental variables, infections markers, and psychosocial factors. RESULTS: Each 20% increase in the proportion of African ancestry was negatively associated with SPT reactivity (OR: 0.79, 95%CI: 0.66-0.96) and positively associated with asthma symptoms in non-atopic individuals (OR: 1.40, 95%CI: 1.03-1.89). We estimated that socioeconomic status and number of infections mediated 28.4% of the effect of African ancestry on SPT reactivity, while 20.2% of the effect on non-atopic asthma was explained by socioeconomic status and behavioral problems in children. CONCLUSIONS: The negative association observed between African ancestry and atopy is most probably explained by unobserved environmental or social factors that covariate with ancestry. For non-atopic asthma, in turn, putative genetic variants of risk underlying African ancestry may play some role.

Biogeographical ancestry is associated with socioenvironmental conditions and infections in a Latin American urban population.

Racial inequalities are observed for different diseases and are mainly caused by differences in socioeconomic status between ethnoracial groups. Genetic factors have also been implicated, and recently, several studies have investigated the association between biogeographical ancestry (BGA) and complex diseases. However, the role of BGA as a proxy for non-genetic health determinants has been little investigated. Similarly, studies comparing the association of BGA and self-reported skin colour with these determinants are scarce. Here, we report the association of BGA and self-reported skin colour with socioenvironmental conditions and infections. We studied 1246 children living in a Brazilian urban poor area. The BGA was estimated using 370,539 genome-wide autosomal markers. Standardised questionnaires were administered to the children's guardians to evaluate socioenvironmental conditions. Infection (or pathogen exposure) was defined by the presence of positive serologic test results for IgG to seven pathogens (Toxocara spp, Toxoplasma gondii, Helicobacter pylori, and hepatitis A, herpes simplex, herpes zoster and Epstein-Barr viruses) and the presence of intestinal helminth eggs in stool samples (Ascaris lumbricoides and Trichiuris trichiura). African ancestry was negatively associated with maternal education and household income and positively associated with infections and variables, indicating poorer housing and living conditions. The self-reported skin colour was associated with infections only. In stratified analyses, the proportion of African ancestry was associated with most of the outcomes investigated, particularly among admixed individuals. In conclusion, BGA was associated with socioenvironmental conditions and infections even in a low-income and highly admixed population, capturing differences that self-reported skin colour miss. Importantly, our findings suggest caution in interpreting significant associations between BGA and diseases as indicative of the genetic factors involved.

Influence of pharmacogenetic polymorphisms and demographic variables on metformin pharmacokinetics in an admixed Brazilian cohort.

AIMS: To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort. METHODS: The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry. Two-step (univariate followed by multivariate) regression modelling was developed to identify covariates associated with systemic exposure to metformin, accessed by the area under the plasma concentration-time curve, between 0 and 48 h (AUC0-48h ), after single oral doses of metformin (500 or 1000 mg). RESULTS: The individual proportions of African, Amerindian and European ancestry varied widely, as anticipated from the structure of the Brazilian population The dose-adjusted, log-transformed AUC0-48h 's (ng h ml-1  mg-1 ) differed largely in the two groups at the opposite ends of the distribution histogram, namely 0.82, 0.79-0.85 and 1.08, 1.06-1.11 (mean, 95% confidence interval; P = 6.10-26 , t test). Multivariate modelling revealed that metformin AUC0-48h increased with age, food and carriage of rs12208357 in SLC22A1 but was inversely associated with body surface area and individual proportions of African ancestry. CONCLUSIONS: A pharmacogenetic marker in OCT1 (SLC22A1 rs12208357), combined with demographic covariates (age, body surface area and individual proportion of African ancestry) and a food effect explained 29.7% of the variability in metformin AUC0-48h .

Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin.

BY VIRTUE OF BEING THE PRODUCT OF THE GENETIC ADMIXTURE OF THREE ANCESTRAL ROOTS: Europeans, Africans, and Amerindians, the present-day Brazilian population displays very high levels of genomic diversity, which have important pharmacogenetic/-genomic (PGx) implications. Recognition of this fact has prompted the creation of the Brazilian Pharmacogenomics Network (Refargen), a nationwide consortium of research groups, with the mission to provide leadership in PGx research and education in Brazil, with a population heath impact. Here, we present original data and review published results from a Refargen comprehensive study of the distribution of PGx polymorphisms in a representative cohort of the Brazilian people, comprising 1,034 healthy, unrelated adults, self-identified as white, brown, or black, according to the Color categories adopted by the Brazilian Census. Multinomial log-linear regression analysis was applied to infer the statistical association between allele, genotype, and haplotype distributions among Brazilians (response variables) and self-reported Color, geographical region, and biogeographical ancestry (explanatory variables), whereas Wright's F(ST) statistics was used to assess the extent of PGx divergence among different strata of the Brazilian population. Major PGx implications of these findings are: first, extrapolation of data from relatively well-defined ethnic groups is clearly not applicable to the majority of Brazilians; second, the frequency distribution of polymorphisms in several pharmacogenes of clinical relevance (e.g., ABCB1, CYP3A5, CYP2C9, VKORC) varies continuously among Brazilians and is not captured by race/Color self-identification; third, the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of PGx studies in order to avoid spurious conclusions based on improper matching of study cohorts.

Pharmacogenetics in the brazilian population.

Brazil is the fifth largest country in the world and its present population, in excess of 190;million, is highly heterogeneous, as a result of centuries of admixture between Amerindians, Europeans, and Sub-Saharan Africans. The estimated individual proportions of biogeographical ancestry vary widely and continuously among Brazilians: most individuals, irrespective of self-identification as White, Brown or Black - the major categories of the Brazilian Census "race/color" system - have significant degrees of European and African ancestry, while a sizeable number display also Amerindian ancestry. These features have important pharmacogenetic (PGx) implications: first, extrapolation of PGx data from relatively well-defined ethnic groups is clearly not applicable to the majority of Brazilians; second, the frequency distribution of polymorphisms in pharmacogenes (e.g., CYP3A5, CYP2C9, GSTM1, ABCB1, GSTM3, VKORC, etc) varies continuously among Brazilians and is not captured by race/color self-identification; third, the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of PGx studies in order to avoid spurious conclusions based on improper matching of study cohorts. The peculiarities of PGx in Brazilians are illustrated with data for different therapeutic groups, such as anticoagulants, HIV protease inhibitors and non-steroidal antinflammatory drugs, and the challenges and advantages created by population admixture for the study and implementation of PGx are discussed. PGx data for Amerindian groups and Brazilian-born, first-generation Japanese are presented to illustrate the rich diversity of the Brazilian population. Finally, I introduce the reader to the Brazilian Pharmacogenetic Network or Refargen, a nation-wide consortium of research groups, with the mission to provide leadership in PGx research and education in Brazil, with a population health impact.

Pharmacogenetics in the Brazilian population

Brazil is the fifth largest country in the world and its present population, in excess of 190 million, is highly heterogeneous, as a result of centuries of admixture between Amerindians, Europeans, and Sub-Saharan Africans. The estimated individual proportions of biogeographical ancestry vary widely and continuously among Brazilians: most individuals, irrespective of self-identification as White, Brown or Black – the major categories of the Brazilian Census “race/color” system – have significant degrees of European and African ancestry, while a sizeable number display also Amerindian ancestry. These features have important pharmacogenetic (PGx) implications: first, extrapolation of PGx data from relatively well-defined ethnic groups is clearly not applicable to the majority of Brazilians; second, the frequency distribution of polymorphisms in pharmacogenes (e.g., CYP3A5, CYP2C9, GSTM1, ABCB1, GSTM3, VKORC, etc) varies continuously among Brazilians and is not captured by race/color self-identification; third, the intrinsic heterogeneity of the Brazilian population must be acknowledged in the design and interpretation of PGx studies in order to avoid spurious conclusions based on improper matching of study cohorts. The peculiarities of PGx in Brazilians are illustrated with data for different therapeutic groups, such as anticoagulants, HIV protease inhibitors and non-steroidal antinflammatory drugs, and the challenges and advantages created by population admixture for the study and implementation of PGx are discussed. PGx data for Amerindian groups and Brazilian-born, first-generation Japanese are presented to illustrate the rich diversity of the Brazilian population. Finally, I introduce the reader to the Brazilian Pharmacogenetic Network or Refargen1, a nation-wide consortium of research groups, with the mission to provide leadership in PGx research and education in Brazil, with a population health impact.