Apolipoproteína E e a doença de Alzheimer

It is known that polymorphisms in the gene of the apolipoprotein E (apoE) are important risk factors in the development of the Alzheimer's disease (AD). The human gene apoE, which is mapped in the long arm of chromosome 19 (19q13.2), codes for a glycoprotein with 317 amino acids, which plays a basic role for the catabolism of triglyceride-rich components in the human body. In our species the apoE gene appears in the form of three main alleles, produced from two alterations in the DNA sequence, called epsilon2, epsilon3 and epsilon4. The identification of the variant epsilon4 of gene apoE as the most relevant genetic marker for the risk for late-onset AD suggests that cholesterol may have a direct involvement in the patho­genesis of this disease. However, apoE epsilon4 is not necessary nor enough to cause Alzheimer's disease. It only increases the risk of an individual to develop the illness, indicating that other environmental/genetic factors shoud play important roles in the development of the disease.Sabemos hoje que os polimorfismos no gene da apolipoproteína E (apoE) são importantes fatores de risco para o desenvolvimento da doença de Alzheimer (DA). O gene apoE humano, mapeado no braço longo do cromossomo 19 (19q13.2), codifica uma glicoproteína com 317 aminoácidos, a qual desempenha um papel fundamental para o catabolismo de componentes ricos em triglicérides no corpo humano. Em humanos, existem três alelos principais do gene apoE, decorrentes de apenas duas alterações no DNA, chamados de épsilon2, épsilon3 e épsilon4. A identificação da variante épsilon4 do gene apoE como o fator genético de risco mais comum para a DA de início tardio sugere que o colesterol deva ter um papel direto na patogênese da doença. Contudo, a simples presença do alelo apoE épsilon4 não é necessária nem suficiente para causar DA; este alelo apenas aumenta o risco de o indivíduo vir a desenvolver a doença, indicando que existem outros fatores ambientais e genéticos importantes no desenvolvimento da mesma

FARMACOGENÉTICA DE DOENÇAS NEUROLÓGICAS

Once a drug has access to the body of an organism, it plays a role in the determination of the specter of effect as well as in its intensity and duration. The extension with the drugs can be absorbed and carried to some target organ influences in its profile of strength and effect. The genetic variation can potentially affect the way an individual reply to the drug in some steps. The absorption of one drugs and its distribution to some organs are processed not only for the physicochemical properties of the drug, but also for endogenous molecules. Many of the susceptibility genes to the illnesses are also target of drugs and can simultaneously predispose the patients to the illness as well as the resistance to the treatment. The identification of new variants for illnesses predisposition can indicate new therapeutical targets and new pathways in the development of drugs and interventions. This systematic characterization of the nature and function of the genetic polymorphisms in enzymes and other advances in the pharmacogenetics has an extensive potential to improve the choice of the appropriate medicine and the correct dose for any patient in particular. In this article, we review the findings in pharmacogenetics of Epilepsy and Alzheimer’s disease.Uma vez que uma droga tenha acesso ao corpo de um organismo, o mesmo desempenha um papel na determinação do espectro de efeitos bem como em sua intensidade e duração. A extensão com que uma droga pode ser absorvida e transportada a vários órgãosalvo influencia no seu perfil de potência e efeito. A variação genética pode potencialm ente afetar a resposta individual à droga em vários passos. A absorção de uma droga e sua distribuição a vários órgãos são processos governados não apenas pelas propriedades físico-químicas da droga, mas também por moléculas endógenas. Muitos dos genes de suscetibilidade a doenças são também alvos de drogas e podem simultaneamente predispor os pacientes à doença bem como à resistência ao tratamento. A identificação de novas variantes para predisposição às doenças pode indicar novos alvos terapêuticos e novas vias no desenvolvimento de drogas e intervenções ambientais. Esta sistemática caracterização da natureza e da função do polimorfismo genético em enzimas metabolizadoras-chave e outros avanços na farmacogenética têm um amplo potencial para melhorar a escolha do medicamento apropriado e a correta dose para qualquer paciente em particular. Nesse artigo, revisamos os achados em farmacogenética na Epilepsia e na Doença de Alzheimer

A quantitative view of the transcriptome of Schistosoma mansoni adult-worms using SAGE

<p>Abstract</p> <p>Background</p> <p>Five species of the genus Schistosoma, a parasitic trematode flatworm, are causative agents of Schistosomiasis, a disease that is endemic in a large number of developing countries, affecting millions of patients around the world. By using SAGE (Serial Analysis of Gene Expression) we describe here the first large-scale quantitative analysis of the Schistosoma mansoni transcriptome, one of the most epidemiologically relevant species of this genus.</p> <p>Results</p> <p>After extracting mRNA from pooled male and female adult-worms, a SAGE library was constructed and sequenced, generating 68,238 tags that covered more than 6,000 genes expressed in this developmental stage. An analysis of the ordered tag-list shows the genes of F10 eggshell protein, pol-polyprotein, HSP86, 14-3-3 and a transcript yet to be identified to be the five top most abundant genes in pooled adult worms. Whereas only 8% of the 100 most abundant tags found in adult worms of S. mansoni could not be assigned to transcripts of this parasite, 46.9% of the total ditags could not be mapped, demonstrating that the 3 sequence of most of the rarest transcripts are still to be identified. Mapping of our SAGE tags to S. mansoni genes suggested the occurrence of alternative-polyadenylation in at least 13 gene transcripts. Most of these events seem to shorten the 3 UTR of the mRNAs, which may have consequences over their stability and regulation.</p> <p>Conclusion</p> <p>SAGE revealed the frequency of expression of the majority of the S. mansoni genes. Transcriptome data suggests that alternative polyadenylation is likely to be used in the control of mRNA stability in this organism. When transcriptome was compared with the proteomic data available, we observed a correlation of about 50%, suggesting that both transcriptional and post-transcriptional regulation are important for determining protein abundance in S. mansoni. The generation of SAGE tags from other life-cycle stages should contribute to reveal the dynamics of gene expression in this important parasite.</p

Transcriptome analysis of Taenia solium cysticerci using Open reading Frame ESTS (ORESTES)

<p>Abstract</p> <p>Background</p> <p>Human infection by the pork tapeworm <it>Taenia solium </it>affects more than 50 million people worldwide, particularly in underdeveloped and developing countries. Cysticercosis which arises from larval encystation can be life threatening and difficult to treat. Here, we investigate for the first time the transcriptome of the clinically relevant cysticerci larval form.</p> <p>Results</p> <p>Using Expressed Sequence Tags (ESTs) produced by the ORESTES method, a total of 1,520 high quality ESTs were generated from 20 ORESTES cDNA mini-libraries and its analysis revealed fragments of genes with promising applications including 51 ESTs matching antigens previously described in other species, as well as 113 sequences representing proteins with potential extracellular localization, with obvious applications for immune-diagnosis or vaccine development.</p> <p>Conclusion</p> <p>The set of sequences described here will contribute to deciphering the expression profile of this important parasite and will be informative for the genome assembly and annotation, as well as for studies of intra- and inter-specific sequence variability. Genes of interest for developing new diagnostic and therapeutic tools are described and discussed.</p

O genoma humano e as perspectivas para o estudo da esquizofrenia

O seqüenciamento de nosso genoma representa um passo essencial no entendimento da biologia humana e no planejamento racional de pesquisas biomédicas. Contudo, é importante notar que o seqüenciamento de um dado genoma é apenas uma parte de um complexo quebra-cabeças. A informação genética deve ser usada como um "mapa", a partir do qual começamos a compreender a base das doenças e a importância da variação genética através da análise da complexidade e do comportamento das regiões reguladoras, genes e proteínas, funções gênicas e sistemas celulares. Apesar dos enormes esforços para identificar genes de susceptibilidade, os resultados de estudos de genética molecular de esquizofrenia até o momento têm sido modestos. O uso apropriado da genômica poderá ajudar imensamente na elucidação das causas da esquizofrenia, permitindo avaliar o papel de novos genes, das variações genéticas, das formas de splicing alternativo, das variações de expressão gênica e de vias metabólicas de interesse. A convergência de dados bioquímicos, de imagem, de neuroanatomia, farmacológicos, clínicos e genéticos permite prever que estamos muito próximos de uma melhor compreensão das bases biológicas da esquizofrenia. A disponibilidade desses avanços terá um enorme impacto na pesquisa desta doença.<br>The sequencing of our genome represents an essential step in the comprehension of the human biology and in the rational planning of biomedical research. However, it is important to realize that the sequencing of a genome is only a piece of a complex puzzle. The genetic information must be used as a "map", the starting-point to understand the basis of the diseases and the importance of the genetic variation through the analysis of the complexity and behavior of the regulatory regions, genes and proteins, gene functions and cellular systems. Despite the enormous efforts made towards the identification of susceptibility genes for schizophrenia, the results of molecular genetics studies have been modest. The appropriate use of genomics should add more information to help the elucidation of the causes of the schizophrenia, supporting areas such as gene discovery, determination of genetic variations, alternative splicing, analysis of diferential gene expression and in the study of metabolic pathways of interest. The convergence of data from studies of biochemistry, imaging, neuroanatomy, pharmacology, clinical and genetics allows to foresee that we should be near to a better understanding of the biological basis of schizophrenia. The availability of these advances will have a dramatic impact on the research of this disease

Taenia solium DNA is present in the cerebrospinal fluid of neurocysticercosis patients and can be used for diagnosis

Neurocysticercosis is the most frequent parasitic infection of the CNS and the main cause of acquired epilepsy worldwide. Seizures are the most common symptoms of the disease, together with headache, involuntary movements, psychosis and a global mental deterioration. Absolute diagnostic criteria include the identification of cysticerci, with scolex, in the brain by MRI imaging. We demonstrate here, for the first time, that T. solium DNA is present in the cerebrospinal fluid of patients. The PCR amplification of the parasite DNA in the CSF enabled the correct identification of 29/30 cases (96.7 %). The PCR diagnosis of parasite DNA in the CSF may be a strong support for the diagnosis of neurocysticercosis

Transcriptome analysis of Taenia solium cysticerci using Open Reading Frama ESTs (ORESTES)

Background: Human infection by the pork tapeworm Taenia solium affects more than 50 million people worldwide, particularly in underdeveloped and developing countries. Cysticercosis which arises from larval encystation can be life threatening and difficult to treat. Here, we investigate for the first time the transcriptome of the clinically relevant cysticerci larval form. Results: Using Expressed Sequence Tags (ESTs) produced by the ORESTES method, a total of 1,520 high quality ESTs were generated from 20 ORESTES cDNA mini-libraries and its analysis revealed fragments of genes with promising applications including 51 ESTs matching antigens previously described in other species, as well as 113 sequences representing proteins with potential extracellular localization, with obvious applications for immune-diagnosis or vaccine development. Conclusion: The set of sequences described here will contribute to deciphering the expression profile of this important parasite and will be informative for the genome assembly and annotation, as well as for studies of intra- and inter-specific sequence variability. Genes of interest for developing new diagnostic and therapeutic tools are described and discussed

Influence of Genomic Ancestry on the Distribution of SLCO1B1, SLCO1B3 and ABCB1 Gene Polymorphisms among Brazilians

The frequency distribution of SNPs and haplotypes in the ABCB1, SLCO1B1 and SLCO1B3 genes varies largely among continental populations. This variation can lead to biases in pharmacogenetic studies conducted in admixed populations such as those from Brazil and other Latin American countries. The aim of this study was to evaluate the influence of self-reported colour, geographical origin and genomic ancestry on distributions of the ABCB1, SLCO1B1 and SLCO1B3 polymorphisms and derived haplotypes in admixed Brazilian populations. A total of 1039 healthy adults from the north, north-east, south-east and south of Brazil were recruited for this investigation. The c.388A&gt;G (rs2306283), c.463C&gt;A (rs11045819) and c.521T&gt;C (rs4149056) SNPs in the SLCO1B1 gene and c.334T&gt;G (rs4149117) and c.699G&gt;A (rs7311358) SNPs in the SLCO1B3 gene were determined by Taqman 5'-nuclease assays. The ABCB1 c.1236C&gt;T (rs1128503), c.2677G&gt;T/A (rs2032582) and c.3435C&gt;T (rs1045642) polymorphisms were genotyped using a previously described single-base extension/termination method. The results showed that genotype and haplotype distributions are highly variable among populations of the same self-reported colour and geographical region. However, genomic ancestry showed that these associations are better explained by a continuous variable. The influence of ancestry on the distribution of alleles and haplotype frequencies was more evident in variants with large differences in allele frequencies between European and African populations. Design and interpretation of pharmacogenetic studies using these transporter genes should include genomic controls to avoid spurious conclusions based on improper matching of study cohorts from Brazilian populations and other highly admixed populations.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), BrazilFinanciadora de Estudos e Projetos (FINEP, Brazil)Financiadora de Estudos e Projetos (FINEP), Brazi