RESUMO
Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity.
Assuntos
Arritmias Cardíacas/etiologia , Morte Súbita/etiologia , Predisposição Genética para Doença , Variantes Farmacogenômicos , Adolescente , Adulto , Canalopatias/genética , Criança , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Canal de Potássio ERG1/genética , Feminino , Variação Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Adulto JovemRESUMO
Camuy River Cave Park (CRCP) is an underground cave system located at the subtropical karst carved by the Camuy River in the subtropical moist forest of northern Puerto Rico (Nieves-Rivera, 2003) [1]. This article contains a metagenomic dataset from the microbial and functional diversity of Clara Cave and Empalme Sinkhole water samples. The environmental DNA (eDNA) from the samples was extracted following direct Metagenomic DNA Isolation method, followed by Next-Generation-Sequencing technology (Illumina MiSeq). The sequences were submitted to MG-RAST online server for taxonomic profile generation and functional in silico description of the samples. The data consisted of domain Bacteria (96.69%), followed up by Viruses (2.87%), Eukaryotes (0.37%), and Archaea (0.02%). The data distribution by phyla showed Proteobacteria (92.61%), Bacteroidetes (1.66%), Actinobacteria (1.12%), and Firmicutes (0.48%). The subsystem functional data showed that 12.97% of genes were related to clustering-based subsystems, 11.40% to carbohydrates, and 11.0% to amino acids and derivatives. The metagenome dataset generated will provide an understanding and comparison framework of the microbial composition and functional diversity present in caves.
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Background and objectives: Mortality of patients on hemodialysis (HD) remains very high despite recent improvements in HD techniques. Cardiovascular (CV) complications and infections are the main causes of death. Some studies suggest that disturbances in the immune system could play a role in this disproportionate mortality, through the links of immunity with inflammation and propensity to infections. However, few studies have addressed the role of lymphocyte populations and the global and CV mortality of HD patients. Aim: To analyze the relationship of peripheral blood lymphocyte populations (PBLP) and all-cause and CV mortality of HD patients. Design setting participants and measurements: We design a prospective observational single center study in a cohort of HD prevalent patients. PBLP were analyzed at baseline and after 1 year and patients were followed for a 5-year period. Main outcomes were all-cause and CV mortality. Results: One hundred and four patients (51% male, mean age 64.8 ± 15 years) were included. Follow-up was 18 (7-47) months. Fifty-five patients (52.8%) died, main causes of death being CVD (40%) and infections (29.1%). Low total lymphocyte counts were found in 47 patients (45.2%), and the most frequency lymphopenias were CD19+ B-cell (57.7%), CD3+ (40.4%), and CD4+ (36.5%). After 1 year, all determinations were lower except CD56+CD16+CD3- natural killer. Patient survival was significantly lower in patients with a CD19+ B-cell count < 100 cells/µL at baseline as compared to patients with CD19+ B-cell ≥ 100 cells/µL counts at the end of follow-up (16.5 vs 54%, p = 0.003). By multivariable analysis, age, history of CV disease, Charlson index, a KT/V < 1.2, and a CD19+ B-cell count < 100 cells/µL at baseline and after 1-year were factors associated with of all-cause mortality. A CD19+ B-cell count < 100 cells/µL at baseline was associated with CV mortality. Conclusion: CD19+ B-cell lymphopenia is very common among HD patients, and it could be an independent predictor of all-cause and CV mortality. More studies are needed to confirm these findings.
Assuntos
Antígenos CD19/metabolismo , Linfócitos B/metabolismo , Biomarcadores , Contagem de Linfócitos , Diálise Renal/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Causas de Morte , Proteínas do Sistema Complemento/imunologia , Feminino , Humanos , Imunoglobulinas/sangue , Estimativa de Kaplan-Meier , Falência Renal Crônica/sangue , Falência Renal Crônica/imunologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Mortalidade , Avaliação de Resultados da Assistência ao Paciente , PrognósticoRESUMO
Recently, there has been much debate about what kinds of genetic markers should be implemented as new core loci that constitute national DNA databases. The choices lie between conventional STRs, ranging in size from 100 to 450 bp; mini-STRs, with amplicon sizes less than 200 bp; and single nucleotide polymorphisms (SNPs). There is general agreement by the European DNA Profiling Group (EDNAP) and the European Network of Forensic Science Institutes (ENFSI) that the reason to implement new markers is to increase the chance of amplifying highly degraded DNA rather than to increase the discriminating power of the current techniques. A collaborative study between nine European and US laboratories was organised under the auspices of EDNAP. Each laboratory was supplied with a SNP multiplex kit (Foren-SNPs) provided by the Forensic Science Service, two mini-STR kits provided by the National Institute of Standards and Technology (NIST) and a set of degraded DNA stains (blood and saliva). Laboratories tested all three multiplex kits, along with their own existing DNA profiling technique, on the same sets of degraded samples. Results were collated and analysed and, in general, mini-STR systems were shown to be the most effective. Accordingly, the EDNAP and ENFSI working groups have recommended that existing STR loci are reengineered to provide smaller amplicons, and the adoption of three new European core loci has been agreed.
Assuntos
Degradação Necrótica do DNA , Impressões Digitais de DNA/métodos , Genética Forense/métodos , Polimorfismo de Nucleotídeo Único , Sequências de Repetição em Tandem , Análise de Variância , Sangue , Europa (Continente) , Genótipo , Humanos , Reação em Cadeia da Polimerase , SalivaRESUMO
A collaborative work was carried out by the Spanish and Portuguese ISFG Working Group (GEP-ISFG) to estimate Y-STR mutation rates. Seventeen Y chromosome STR loci (DYS19, DYS385, DYS389I and II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS460, DYS461, DYS635 [GATA C4], GATA H4, and GATA A10) were analyzed in a sample of 3,026 father/son pairs. Among 27,029 allele transfers, 54 mutations were observed, with an overall mutation rate across the 17 loci of 1.998 x 10(-3) (95% CI, 1.501 x 10(-3) to 2.606 x 10(-3)). With just one exception, all of the mutations were single-step, and they were observed only once per gametogenesis. Repeat gains were more frequent than losses, longer alleles were found to be more mutable, and the mutation rate seemed to increase with the father's age. Hum Mutat 26(6), 520-528, 2005. (c) 2005 Wiley-Liss, Inc.
Assuntos
Cromossomos Humanos Y/genética , Repetições de Microssatélites/genética , Mutação , Fatores Etários , Alelos , Sequência de Bases , Análise Mutacional de DNA , Frequência do Gene , Marcadores Genéticos , Humanos , Masculino , Dados de Sequência MolecularRESUMO
French population, despite of its crucial geographic location for repopulation movements of Europe across time, it has been insufficiently characterized at the genetic level, especially for Y-chromosomal DNA variation. In order to make a genetic structure characterization, we have analyzed the Y-chromosome diversity of 558 male individuals, scattered along 7 different French regions: Alsace (Strasbourg), Auvergne (Clermont-Ferrand), Bretagne (Rennes), Île-de-France (Paris), Midi-Pyrénées (Toulouse), Nord-Pas-de-Calais (Lille) and Provence-Alpes-Côte d'Azur (Marseille). A total of 17 Y-chromosome STRs and 27 Y-chromosome SNPs were genotyped for each individual. Even though we find that most of the individual populations in France were not differentiated from each other, Bretagne population shows population substructure, an important fact to be considered when establishing general population databases.
Assuntos
Cromossomos Humanos Y/genética , Impressões Digitais de DNA , Repetições de Microssatélites , França , Genética Populacional , Genótipo , Haplótipos , Humanos , Masculino , Reação em Cadeia da Polimerase MultiplexRESUMO
Using a 52 SNP marker set previously developed for forensic analysis, a novel 49plex assay has been developed based on the Genplex typing system, a modification of SNPlex chemistry (both Applied Biosystems) using oligo-ligation of pre-amplified DNA and dye-labeled, mobility modified detection probes. This gives highly predictable electrophoretic mobility of the allelic products generated from the assay to allow detection with standard capillary electrophoresis analyzers. The loci chosen comprise the 48 most informative autosomal SNPs from the SNPforID core discrimination set supplemented with the amelogenin gender marker. These SNPs are evenly distributed across all 22 autosomes, exhibit balanced polymorphisms in three major population groups and have been previously shown to be effective markers for forensic analysis. We tested the accuracy and reproducibility of the Genplex system in three SNPforID laboratories, each using a different Applied Biosystems Genetic Analyzer. Genotyping concordance was measured using replicates of 44 standardized DNA controls and by comparing genotypes for the same samples generated by the TaqMan, SNaPshot and Sequenom iPLEX SNP typing systems. The degree of informativeness of the 48 SNPs for forensic analysis was measured using previously estimated allele frequencies to derive the cumulative match probability and in paternity analysis using 24 trios previously typed with 18 STRs together with three CEPH families with extensive sibships typed with the 15 STRs in the Identifiler kit.