CYP2D6 Allele Frequency in Five Malaria Vivax Endemic Areas From Brazilian Amazon Region

Funding Information: We acknowledge the participants in the study, without whom this research could not have been done. For laboratorial support the authors wish to show their appreciation to Gabriel Barbosa de Abreu (in memorian). To Norman Ratcliffe for the English revision of this manuscript. Part of this work is described in a Master?s Dissertation by PS, conducted at the Applied Microbiology and Parasitology Post-graduation Program, Federal Fluminense University. Publisher Copyright: © Copyright © 2021 Salles, Perce-da-Silva, Rossi, Raposo, Ramirez Ramirez, Pereira Bastos, Pratt-Riccio, Cassiano, Baptista, Cardoso, Banic and Machado.Genetic variability was linked with individual responses to treatment and susceptibility to malaria by Plasmodium vivax. Polymorphisms in the CYP2D6 gene may modulate enzyme level and activity, thereby affecting individual responses to pharmacological treatment. The aim of the study was to investigate whether or not CYP2D6 single nucleotide polymorphisms rs1065852, rs38920-97, rs16947 and rs28371725 are unequally distributed in malaria by Plasmodium vivax individuals from the Brazilian Amazon region. The blood samples were collected from 220 unrelated Plasmodium vivax patients from five different endemic areas. Genotyping was performed using SNaPshot® and real-time polymerase chain reaction methods. In all five areas, the rs1065852 (CYP2D6*10, C.100C > T), rs3892097 (CYP2D6*4, 1846C > T) and rs16947 (CYP2D6*2, C.2850G > A), as a homozygous genotype, showed the lowest frequencies. The rs28371725 (CYP2D6*41, 2988G > A) homozygous genotype was not detected, while the allele A was found in a single patient from Macapá region. No deviations from Hardy-Weinberg equilibrium were found, although a borderline p-value was observed (p = 0.048) for the SNP rs3892097 in Goianésia do Pará, Pará state. No significant associations were detected in these frequencies among the five studied areas. For the SNP rs3892097, a higher frequency was observed for the C/T heterozygous genotype in the Plácido de Castro and Macapá, Acre and Amapá states, respectively. The distribution of the CYP2D6 alleles investigated in the different areas of the Brazilian Amazon is not homogeneous. Further investigations are necessary in order to determine which alleles might be informative to assure optimal drug dosing recommendations based on experimental pharmacogenetics.publishersversionpublishe

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Estudos de associação de polimorfismos de base única em genes candidatos na Hanseníase

Submitted by Repositório Arca ([email protected]) on 2019-07-02T18:37:05Z No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) cynthia_cardoso_ioc_mest_2006.pdf: 1276695 bytes, checksum: 8394bbf5e857ec93dc341eec48701e68 (MD5)Approved for entry into archive by Raquel Dinelis ([email protected]) on 2019-09-23T18:26:32Z (GMT) No. of bitstreams: 2 cynthia_cardoso_ioc_mest_2006.pdf: 1276695 bytes, checksum: 8394bbf5e857ec93dc341eec48701e68 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Made available in DSpace on 2019-09-23T18:26:32Z (GMT). No. of bitstreams: 2 cynthia_cardoso_ioc_mest_2006.pdf: 1276695 bytes, checksum: 8394bbf5e857ec93dc341eec48701e68 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2006Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.A Hanseníase é uma doença infecciosa crônica causada por um patógeno intracellular obrigatório, o Mycobacterium leprae, com tropismo por células de Schwann nos nervos periféricos e macrófagos na pele. O espectro com cinco formas clínicas diferentes é determinado pela interação patógeno-hospedeiro através da influência do M. leprae sobre a resposta imune do hospedeiro associada à dicotomia Th1 x Th2, a qual é representada pelas formas tuberculoides e lepromatosas da doença. A análise de seqüências do M. leprae demonstrou uma baixa variabilidade, de forma que tanto o desenvolvimento de Hanseníase quanto de seu espectro de manifestações depende majoritariamente das características do hospedeiro. Esta observação tem estimulado estudos visando à identificação de marcadores de suscetibilidade à Hanseníase per se ou a uma das formas clínicas. O objetivo deste estudo foi a reprodução de resultados já publicados de associação entre polimorfismos de base única (SNPs) e a suscetibilidade à Hanseníase. Um estudo tipo caso-controle utilizando uma população composta por 233 contatos domiciliares sadios e 212 pacientes de todas as formas clínicas da hanseníase foi desenhado. As amostras foram genotipadas através dos métodos de PCR-RFLP ou discriminação alélica por tempo real para SNPs dos genes TNFA (-308), LTA (+252) e PARK2 (-2599 e rs1040079). Desvios em relação ao Equilíbrio de Hardy-Weinberg foram detectados em SNPs do lócus de TNF (-308 nos contatos e +252 nos pacientes) e no SNP \20132599 do gene PARK2 em ambas as populações. As análises baseadas em populações confirmam a proteção anteriormente detectada para o alelo TNF-308A (OR=0,59; P=0,03) e para o haplótipo \2013308A/+252A, embora este segundo resultado não seja significativo (OR=0,47; P=0,06) Os estudos de SNPs e haplótipos do gene PARK2 não detectaram associação. Um novo SNP (asp110ala) no gene de ninjurina (NINJ1) também foi investigado de modo a verificar uma possível associação com a Hanseníase. Nenhuma evidência de associação deste SNP com a suscetibilidade e severidade foi detectada, embora uma primeira analise tenha sugerido associação com dano neural avaliado pelo grau de incapacidade. Assim utilizando uma população estendida de pacientes (n=765) foi confirmada a associação do alelo 110ala e o grau de incapacidade (OR=1,54; P=0,007). A quantificação alelo-específica dos transcritos por tempo real demonstrou que o alelo 110asp tem expressão aumentada quando comparada à do alelo 110ala. Neste trabalho foi confirmada a associação do alelo -308A com a resistência a hanseníase per se em Brasileiros. As análises de ninjurina demonstraram que o SNP asp110ala pode ser um marcador prognóstico valioso já que o carreadores do alelo 110ala têm suscetibilidade aumentada ao dano neural, possivelmente causada por uma expressão reduzida desta molécula de adesão mediada por esse alelo.Leprosy is a chronic infectious disease caused by the intracellular pathogen Mycobacterium leprae, which has tropism for Schwann cells in peripheral nerves and macrophages in the skin. The spectrum with five different clinical forms is determined by host:pathogen interactions that influences a polarized immune response represented as the tuberculoid and lepromatous forms of the disease, which are associated to Th1 x Th2 immunological patterns, respectively. The sequence analysis of M. leprae showed low genetic variability in a way that both leprosy per se and the spectrum of manifestations are explained mostly due to host responses. This observation has encouraged many studies aiming the identification of markers of susceptibility to leprosy per se or to one of the clinical forms. The aim of this study was to replicate in a new population previous published results that reported association between single nucleotide polymorphisms (SNPs) and leprosy susceptibility. It was designed a casecontrol study using 233 healthy unrelated household contacts and 212 patients from all clinical forms of leprosy. Samples were genotyped using PCR-RFLP or allelic discrimination method for SNPs in TNFA (-308), LTA (+252) and PARK2 (-2599 and rs1040079) genes. Deviations from the Hardy-Weinberg Equilibrium were detected in SNPs located at TNF locus (-308 in patients and +252 in control group) and for the SNP –2599 at PARK2 gene in both populations. The population-based analysis replicated the protection previously reported for allele TNF-308A (OR=0,59; P=0,03) and also for –308A/+252A haplotype, although it was not significant (OR=0,47 P=0,06). Analysis with PARK2 SNPs and haplotypes did not show any association. A novel SNP (asp110ala) at NINJ1 gene was also investigated so as to determine a possible association with leprosy. There was no evidence of association of this SNP and leprosy susceptibility and severity, but the first analysis suggested an association with neurological damage as assessed by the disability grade. So, using an extended patients population (n=765) we confirmed the association between allele 110ala and incapacity grade (OR=1,54; P=0,007). Functional analysis detected a higher ninjurin mRNA and protein expression in response to M. leprae stimulus. Allele-specific transcript quantitation demonstrated that allele 110asp was augmented as compared to 110ala. Here, we confirm the association of -308A allele with resistance of leprosy per se among Brazilians. Ninjurin analysis showed that asp110ala could be a valuable prognostic marker, since carriers of ala110 allele have increased susceptibility to nerve damage possibly because this allele shows a decreased expression of this adhesion molecule

Genetics of host response in leprosy

Submitted by Sandra Infurna ([email protected]) on 2019-07-02T17:26:33Z No. of bitstreams: 1 MiltonOzorio_CynthiaCardoso_etal_IOC_2006.pdf: 225865 bytes, checksum: a18b9a49069b6ae8f04d6d6c6804b31e (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2019-07-02T17:34:28Z (GMT) No. of bitstreams: 1 MiltonOzorio_CynthiaCardoso_etal_IOC_2006.pdf: 225865 bytes, checksum: a18b9a49069b6ae8f04d6d6c6804b31e (MD5)Made available in DSpace on 2019-07-02T17:34:28Z (GMT). No. of bitstreams: 1 MiltonOzorio_CynthiaCardoso_etal_IOC_2006.pdf: 225865 bytes, checksum: a18b9a49069b6ae8f04d6d6c6804b31e (MD5) Previous issue date: 2006Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Mycobacterioses. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Mycobacterioses. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Departamento de Mycobacterioses. Laboratório de Hanseníase. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Departamento de Epidemiologia e Métodos Quantitativos. Rio de Janeiro, RJ, Brasil.In this review, we discuss recently accumulated data, analysing genetic influence on leprosy outcome. Most leprosy-related epidemiological studies are based on the comparison of frequencies of genetic markers in case-control designs using candidate genes, mainly on immunological pathways. Genomic scans using familybased designs also identified some chromosome regions to be tested for association with leprosy. The results have suggested that different genes are implicated in resistance/susceptibility to leprosy, such as tumour necrosis factor-alpha (TNFa), interleukin (IL)-10, vitamin D receptor (VDR), and parkin, although some of the results obtained in different populations are controversial. In spite of the recent advances in genomics and genetic epidemiology we have experienced, the results must be confirmed using better designed epidemiological studies to directly pinpoint the genes responsible for leprosy outcome. Furthermore, there is a clear requirement of functional/biological data in order to validate epidemiological findings. In this way, these genetic markers could be used to screen high-risk populations introducing gene testing as diagnostic and prognostic tools to interrupt the chain of transmission and prevent neurological damage

Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals

<div><p>Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at <i>SLCO2B1</i> was associated to intolerance to NRTIs (OR_GA/AA = 2.37; p = 0.0001), while rs4148396, at <i>ABCC2</i>, conferred risk of intolerance to PIs containing regimens (OR_CT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies.</p></div

Association between <i>SLCO2B1</i> gene and intolerance to nucleoside reverse transcriptase inhibitors.

<p>Association between <i>SLCO2B1</i> gene and intolerance to nucleoside reverse transcriptase inhibitors.</p

Association between <i>ABCC2</i> gene and intolerance to protease inhibitors.

<p>Association between <i>ABCC2</i> gene and intolerance to protease inhibitors.</p

CARACTERÍSTICAS CLÍNICO-EPIDEMIOLÓGICAS DE PACIENTES COM COVID-19 ATENDIDOS NO NEEDIER/UFRJ EM DIFERENTES ONDAS DE VARIANTES VIRAIS

Introdução/Objetivo: O NEEDIER (Núcleo de Enfrentamento e Estudos de Doenças Infecciosas Emergentes e Reemergentes) foi importante para o diagnóstico da covid-19 na comunidade da UFRJ e profissionais de saúde e segurança pública. Ao longo da pandemia, notaram-se mudanças nas características e sintomas do público atendido, associados às ondas causadas por diferentes variantes do vírus. O presente estudo tem como objetivo avaliar as características clínicas e epidemiológicas da população com diagnóstico de covid-19 atendida no NEEDIER nesses diversos períodos. Métodos: Coorte de indivíduos diagnosticados com covid-19 no NEEDIER. Os indivíduos foram triados e testados por meio de RT-PCR em swab de nasofaringe. Características clínico-epidemiológicas foram coletadas a partir de questionário. Os pacientes assinaram TCLE para participação no projeto (CAAE: 30161620.0.1001.5257). Ondas de variantes foram definidas com os dados estaduais de sequenciamento disponíveis no GISAID. Resultados: Entre 16/mar/2020 e 31/dez/2022, 7931 indivíduos foram diagnosticados com covid-19. No período, quatro variantes virais causaram ondas delimitadas da doença: original (3756 casos), Gama (752), Delta (412) e Omicron (2554). Houve predominância de mulheres em todos os períodos (59, 48, 58 e 61%, respectivamente, p = 0,46). A idade mediana foi de 38, 37, 35 e 32 anos (p 98%). Os sintomas apresentados mudaram ao longo das diferentes ondas, destacando a importância da atualização de critérios de triagem para um diagnóstico precoce

Association between MBL2 haplotypes and dengue severity in children from Rio de Janeiro, Brazil

Submitted by Fábio Marques ([email protected]) on 2019-06-10T19:10:10Z No. of bitstreams: 1 Association between MBL2_Marcelo_Ribeiro-Alves_INI_Lapclin-AIDS_2019.pdf: 384337 bytes, checksum: d9a3472dc639201787afe938b04a6ea6 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-06-10T19:34:37Z (GMT) No. of bitstreams: 1 Association between MBL2_Marcelo_Ribeiro-Alves_INI_Lapclin-AIDS_2019.pdf: 384337 bytes, checksum: d9a3472dc639201787afe938b04a6ea6 (MD5)Made available in DSpace on 2019-06-10T19:34:37Z (GMT). No. of bitstreams: 1 Association between MBL2_Marcelo_Ribeiro-Alves_INI_Lapclin-AIDS_2019.pdf: 384337 bytes, checksum: d9a3472dc639201787afe938b04a6ea6 (MD5) Previous issue date: 2019Universidade Federal do Rio de Janeiro. Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST-AIDS. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro, Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biologia. Departamento de Genética. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil.BACKGROUND: Dengue is an arthropod-borne viral disease with a majority of asymptomatic individuals and clinical manifestations varying from mild fever to severe and potentially lethal forms. An increasing number of genetic studies have outlinedthe association between host genetic variations and dengue severity. Genes associated to viral recognition and entry, as well as those encoding mediators of the immune response against infection are strong candidates for association studies. OBJECTIVES: The aim of this study was to investigate the association between MBL2, CLEC5A, ITGB3 and CCR5 genes and dengue severity in children. METHODS: A matched case-control study was conducted and 19 single nucleotide polymorphisms (SNPs) were investigated. FINDINGS: No associations were observed in single SNP analysis. However, when MBL2 SNPs were combined in haplotypes, the allele rs7095891G/rs1800450C/ rs1800451C/rs4935047A/rs930509G/rs2120131G/rs2099902C was significantly associated to risk of severe dengue under α = 0.05 (aOR = 4.02; p = 0.02). A second haplotype carrying rs4935047G and rs7095891G alleles was also associated to risk (aOR = 1.91; p = 0.04). MAIN CONCLUSIONS: This is the first study to demonstrate the association between MBL2 haplotypes and dengue severity in Brazilians including adjustment for genetic ancestry. These results reinforce the role of mannose binding lectin in immune response to DENV