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

Pharmacogenetic testing in oncology: a Brazilian perspective

Pharmacogenetics, a major component of individualized or precision medicine, relies on human genetic diversity. The remarkable developments in sequencing technologies have revealed that the number of genetic variants modulating drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to rare mutations (minor allele frequency, MAFo1%) in addition to polymorphisms (MAF41%) in pharmacogenes. This has major implications for the conceptual development and clinical implementation of pharmacogenetics. Drugs used in cancer treatment have been major targets of pharmacogenetics studies, encompassing both germline polymorphisms and somatic variants in the tumor genome. The present overview, however, has a narrower scope and is focused on germline cancer pharmacogenetics, more specifically, on drug/gene pairs for which pharmacogenetics-informed prescription guidelines have been published by the Clinical Pharmacogenetics Implementation Consortium and/or the Dutch Pharmacogenetic Working Group, namely, thiopurines/TPMT, fluoropyrimidines/UGT1A1, irinotecan/UGT1A1 and tamoxifen/CYP2D6. I begin by reviewing the general principles of pharmacogenetics-informed prescription, pharmacogenetics testing and the perceived barriers to the adoption of routine pharmacogenetics testing in clinical practice. Then, I highlight aspects of the pharmacogenetics testing of the selected drug-gene pairs and finally present pharmacogenetics data from Brazilian studies pertinent to these drug-gene pairs. I conclude with the notion that pharmacogenetics testing has the potential to greatly benefit patients by enabling precision medicine applied to drug therapy, ensuring better efficacy and reducing the risk of adverse effects

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

Ether à go-go potassium channel expression in soft tissue sarcoma patients

BACKGROUND: The expression of the human Eag1 potassium channel (Kv10.1) is normally restricted to the adult brain, but it has been detected in both tumour cell lines and primary tumours. Our purpose was to determine the frequency of expression of Eag1 in soft tissue sarcoma and its potential clinical implications. RESULTS: We used specific monoclonal antibodies to determine the expression levels of Eag1 in soft tissue sarcomas from 210 patients by immunohistochemistry. Eag1 was expressed in 71% of all tumours, with frequencies ranging from 56% (liposarcoma) to 82% (rhabdomyosarcoma). We detected differences in expression levels depending on the histological type, but no association was seen between expression of this protein and sex, age, grade or tumour size. Four cell lines derived from relevant sarcoma histological types (fibrosarcoma and rhabdomyosarcoma) were tested for Eag1 expression by real-time RT-PCR. We found all four lines to be positive for Eag1. In these cell lines, blockage of Eag1 by RNA interference led to a decrease in proliferation. CONCLUSION: Eag1 is aberrantly expressed in over 70% sarcomas. In sarcoma cell lines, inhibition of Eag1 expression and/or function leads to reduced proliferation. The high frequency of expression of Eag1 in primary tumours and the restriction of normal expression of the channel to the brain, suggests the application of this protein for diagnostic or therapeutic purposes

Study of membrane potential in T lymphocytes subpopulations using flow cytometry

<p>Abstract</p> <p>Background</p> <p>Ion channels are involved in the control of membrane potential (ψ) in a variety of cells. The maintenance of ψ in human T lymphocytes is essential for T-cell activation and was suggested to depend mostly on the voltage-gated Kv1.3 channel. Blockage of Kv1.3 inhibits cytokine production and lymphocyte proliferation <it>in vitro </it>and suppresses immune response <it>in vivo</it>. T lymphocytes are a heterogeneous cell population and the expression of Kv1.3 varies among cell subsets. Oxonol diBA-C4-(3) was used to determine ψ by flow cytometry. The presence of distinct T cell subsets was evaluated by immunophenotyping techniques and the contribution of Kv1.3 channels for the maintenance of ψ was investigated using selective blockers.</p> <p>Results</p> <p>The distribution of ψ in T lymphocytes varied among blood donors and did not always follow a unimodal pattern. T lymphocytes were divided into CD3⁺/CD45RO^-and CD3⁺/CD45RO⁺subsets, whose peak channel values of ψ were -58 ± 3.6 mV and -37 ± 4.1 mV, respectively. MgTX (specific inhibitor of Kv1.3 channels) had no significant effect in the ψ of CD3⁺/CD45RO^-subsets but depolarized CD3⁺/CD45RO⁺cells to -27 ± 5.1 mV.</p> <p>Conclusion</p> <p>Combination of optical methods for determination of ψ by flow cytometry with immuophenotyping techniques opens new possibilities for the study of ion channels in the biology of heterogeneous cell populations such as T lymphocyte subsets.</p

The Genomic Ancestry of Individuals from Different Geographical Regions of Brazil Is More Uniform Than Expected

Based on pre-DNA racial/color methodology, clinical and pharmacological trials have traditionally considered the different geographical regions of Brazil as being very heterogeneous. We wished to ascertain how such diversity of regional color categories correlated with ancestry. Using a panel of 40 validated ancestry-informative insertion-deletion DNA polymorphisms we estimated individually the European, African and Amerindian ancestry components of 934 self-categorized White, Brown or Black Brazilians from the four most populous regions of the Country. We unraveled great ancestral diversity between and within the different regions. Especially, color categories in the northern part of Brazil diverged significantly in their ancestry proportions from their counterparts in the southern part of the Country, indicating that diverse regional semantics were being used in the self-classification as White, Brown or Black. To circumvent these regional subjective differences in color perception, we estimated the general ancestry proportions of each of the four regions in a form independent of color considerations. For that, we multiplied the proportions of a given ancestry in a given color category by the official census information about the proportion of that color category in the specific region, to arrive at a “total ancestry” estimate. Once such a calculation was performed, there emerged a much higher level of uniformity than previously expected. In all regions studied, the European ancestry was predominant, with proportions ranging from 60.6% in the Northeast to 77.7% in the South. We propose that the immigration of six million Europeans to Brazil in the 19th and 20th centuries - a phenomenon described and intended as the “whitening of Brazil” - is in large part responsible for dissipating previous ancestry dissimilarities that reflected region-specific population histories. These findings, of both clinical and sociological importance for Brazil, should also be relevant to other countries with ancestrally admixed populations