DPSPDNT - Posters/abstracts em congressos nacionais
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- Co-relação entre perfil lipídico/risco cardiovascular e tipo de mutação em doentes com Hipercolesterolemia FamiliarPublication . Alves, A.C.; Medeiros, A.M.; Bourbon, M.A Hipercolesterolemia Familiar (FH) é uma doença autossómica dominante que se caracteriza a nível clínico por níveis elevados de LDLc, levando ao aparecimento prematuro de doenças cardiovasculares. A nível genético esta doença caracteriza-se por mutações em três genes: LDLR, APOB e PCSK9. O fenótipo de doentes com mutações nestes 3 genes é variável, estando descrito que doentes (dts) com mutações no gene PCSK9 apresentam um fenótipo mais grave e dts com mutação no gene APOB apresentam o fenótipo menos grave. Diferentes mutações no gene LDLR estão também associadas a diferentes fenótipos. Consequentemente o risco cardiovascular destes dts varia de acordo com a severidade do fenótipo apresentado por cada um. O objectivo deste estudo foi analisar o perfil bioquímico de dts com FH diagnosticada geneticamente de acordo com as mutações encontradas nos diferentes genes e com os diferentes tipos de mutações identificadas no gene LDLR para identificar se existe uma co-relação entre estas variáveis nos dts portugueses. Os parâmetros bioquímicos, colesterol total (CT), LDLc, HDLc, trigliceridos, ApoB e ApoAI) de 325 dts (225 adultos e 100 crianças) com FH foram analisados por SPSS, utilizando os testes ANOVA e de Tukey. Doentes com mutação no gene PCSK9 têm valores de CT e LDLc significativamente mais elevados do que dts com mutações nos restantes 2 genes. Não existe diferença significativa nestes parâmetros entre dts com mutações nos genes APOB e LDLR, embora todos os valores sejam mais elevados nos dts com mutações no gene LDLR. Doentes com mutações nonsense no gene LDLR apresentam valores de CT, LDLc e ApoB estatisticamente mais elevados do que dts com mutações missense. A comparação entre as outras categorias de mutações não revelou diferenças significativas nos parâmetros bioquímicos. Doentes com mutações no gene PCSK9 têm um fenótipo mais grave do que dts com mutações nos genes LDLR e APOB, tendo por esta razão um risco cardiovascular mais elevado. Nos dts portugueses com FH não foram observadas diferenças estatisticas significativas entre o fenótipo de dts com mutação nos genes LDLR e APOB. Doentes com mutações nonsense no LDLR que levam à não produção da proteína apresentam um fenótipo mais grave do que dts com mutações no gene LDLR que dão origem uma proteína que retêm alguma funcionalidade (mutações missense e splicing). O tipo de mutação (em diferentes genes ou diferentes mutações no LDLR) é importante para determinar o risco cardiovascular de cada doente.
- Utilidade da Proteómica na Compreensão da Patogenia Molecular Proximal da Doença Cerebral AlcoólicaPublication . Peneda, Jorge; Charro, Nuno; L. Hood, Brian; Fonseca, Aidil; Hagenfeldt, Manuela; Miranda, Armandina; Zerimech, Farid; Gomes, Filomena; Neto, Domingos; P. Conrads, Thomas; Faria, Daniel; M Couto, Francisco; Penque, DeborahO avanço técnico instrumental no estudo da Proteómica permite aprofundar a interpretação da patogenia molecular de múltiplas doenças. Na doença degenerativa cerebral o mecanismo patogénico inflamatório crónico e imunológico tem sido consensual como será o caso deste órgão alvo preferencial estrutural e funcional em circuitos neuronais susceptíveis na doença alcoólica crónica. A perda da quiescência da impermeabilidade da barreira hemato-encefálica na doença alcoólica, torna acessível o estudo de marcadores moleculares proteicos no sangue periférico, com o apoio da bioinformática e cuidado escrutínio abrangente bibliográfico de proteínas selectivas individuais explícitas e, implícitas intervenientes directas/indirectas na disfunção bioquímica da nevróglia (glicose) e da transmissão neural. Objectivo: Valorização interpretativa no comportamento do complexo perfil proteómico electivo na patogenia molecular da doença cerebral sob efeito pró imunoinflamatório sistémico do metabolismo do etanol e endotoxémia na doença cerebral alcoólica (DCA). Material e métodos: Estudo longitudinal de 27 doentes com alcoolismo crónico activo (T0) e valorização comparativa com abstinência controlada (T1) terapêutica, psicologia de grupo e dieta standardizada em dois subgrupos: (A n=17) com elevados níveis relativos de indicadores de stresse oxidativo/nítrico versus (B n=10) com baixos níveis destes indicadores. Métodos laboratoriais – proteómica e bioquímica descrita pelos autores em 4th EuPA Scientific Meeting, A Proteomics Odyssey Towards Next Decades, Estoril, Portugal, October 23-27 2010:110 111. Resultados Sintéticos: Frequência de rácios A/B: 54.2% de 354 proteínas totais descriminadas têm influência directa/indirecta no SNC. Do total, 51.8% aumentadas e 53.1% diminuídas. Evolução de rácios sob abstinência em cada grupo: AT0/AT1 de 146 proteínas 40.4% diminuídas e 59.6% aumentadas; BT0/BT1 de 130 proteínas 50.8% diminuídas e 49.2% aumentadas; e ainda valorização funcional descriminada de proteínas individuais do total de 340. Conclusões: O stresse oxidativo/nítrico altera o perfil proteómico quantitativo e qualitativo sob consumo activo com indiciadores moleculares múltiplos para um estado global pró-inflamatório e pró-apoptoico (glicose e degenerescência neural). A reversibilidade clínica parcial é acompanhada por variações evolutivas quantitativas e qualitativas do perfil proteómico o que permite valorizar a importância do stresse oxidativo/nítrico como indução patogénica molecular proximal na degenerescência da (DCA).
- Caracterização bioquímica e molecular de doentes com hipercolesterolemias genéticasPublication . Alves, A.C.; Medeiros, A.M.; Gomes, A.; Bourbon, M.O colesterol elevado no sangue contribui para o processo arterosclerótico, que está na base das doenças cardiovasculares (DCV). Perturbações no metabolismo lipídico podem dever-se a alterações nos receptores ou seus ligandos, como é o caso da Hipercolesterolemia Familiar (FH). A FH é uma doença autossómica dominante que se caracteriza a nível clínico por níveis elevados de cLDL, levando ao aparecimento prematuro de doenças cardiovasculares. A nível genético esta doença caracteriza-se por mutações em três genes: LDLR, APOB e PCSK9. O objectivo deste estudo foi analisar o perfil bioquímico e molecular de doentes com FH diagnosticada clinicamente e o aparecimento de doença cardiovascular prematura nos doentes referenciados ao Estudo Português de Hipercolesterolemia Familiar (EPFH).
- A Hipercolesterolemia Familiar em crianças: Resultados do Estudo Português de Hipercolesterolemia FamiliarPublication . Medeiros, A.M.; Alves, A.C.; Santos, T.; Bourbon, M.A Hipercolesterolemia Familiar (FH) é uma doença genética do metabolismo do colesterol, caracterizada por valores elevados de c-LDL no plasma, conduzindo a aterosclerose e doença cardiovascular (DCV) prematura. A FH é originada por mutações nos genes: LDLR, APOB e PCSK9. O gene APOE é polimórfico com três alelos frequentes (e2, e3 e e4), originando seis genótipos diferentes e seis isoformas com diferentes afinidades para o receptor das LDL. A isoforma E2 possui menos afinidade enquanto a E4 tem uma ligação mais eficiente e compete com a apoB. O principal objectivo do Estudo Português de Hipercolesterolemia Familiar (EPHF) é identificar doentes com FH de modo a prevenir o desenvolvimento de DCV. Até à data foram estudados 477 casos-índex com diagnóstico clínico de FH, dos quais 162 são crianças. O critério clínico de FH usado foi adaptado de Simon Broome Heart Research Trust (CT>200mg/dl, cLDL>115mg/dl e história familiar de Hipercolesterolemia e/ou DCV).
- Next-generation sequencing of LDLR and APOB genes in patients with a clinical diagnosis of Familial HypercholesterolaemiaPublication . Alves, A.C.; Bourbon, M.Familial hypercholesterolemia (FH) is a genetic condition characterized by a high cholesterol concentration in the blood. The most frequent causes of FH are inherited defects in the Low Density Lipoprotein Receptor gene (LDLR) but, in a small percentage of patients, mutations in the apolipoprotein B gene (APOB) and in the propotein convertase subtilisin/kexin type 9 gene (PCSK9) are also responsible for FH. These 3 genes are currently studied in the “Portuguese FH study”. From the 563 families with a clinical diagnosis of FH studied only 41% of these have a mutation in one of the 3 studied genes, so other gene defects must exist to explain the cause of hypercholesterolemia in the remaining families. The aim of this study was the exclusion of previously unidentified LDLR and APOB gene defects in 65 severely affected patients, as well as the exclusion of mutations in LDLRAP1 and CYP7A1 genes in patients with possible recessive hypercholesterolemia. The whole sequencing of LDLR and APOB genes of the 65 index patients, without mutations in LDLR or PCSK9 genes or in fragments of exon 26 and 29 of APOB gene was performed. A pool of the 65 DNAs was sequenced by pyrosequecing with custom design primers and a total of 227688 nucleotide reads were obtained, corresponding to a mean coverage of 35x/fragment/individual. CYP7A1 and LDLRAP1 genes were analysed by PCR and direct sequencing. A total of 87 alterations were detected by pyrosequencing. More than half were previously described SNPs and 32 were novel possible pathogenic variants. The majority of these variants (25) were in exons 26 and 29. From the 32 novel variations identified by pyrosequencing only 4 were found by Sanger sequencing. Three alterations (2 novel and 1 described) were found by Sanger sequencing and were not detected by pyrosequencing. Three SNP’s were also studied do to their low alleles estimated. After family studies of these 10 variants, 3 alterations did not co-segregate in the family, 4 alterations were not possible to verify co-segregation and 3 of the alterations found are possibly mutations causing disease, but functional studies are required to prove pathogenicity. No mutations were found in LDLRAP1 and CYP7A1 genes in 10 patients with possible recessive hypercholesterolemia. Patients, in whom it was not possible to find the genetic cause of the hypercholesterolaemia, will require further studies, since all show a severe clinical phenotype of FH.
- A genome-wide association study using a DNA pooling strategy identifies BBS9 and GLIS3 as novel loci influencing patient’s outcome after strokePublication . Manso, H.; Paulos-Pinheiro, S.; Krug, T.; Sobral, J.; Albergaria, I.; Gaspar, G.; Ferro, J.M.; Oliveira, S.A.; Vicente, A.M.Stroke is a major cause of morbidity in developed countries and therefore finding adequate treatments to promote patient’s recovery is a priority task, requiring the elucidation of the molecular pathways influencing brain recovery. Few studies, however, have assessed the role of genes in stroke outcome. This study describes a pilot genome-wide association study (GWAS) to identify genetic factors contributing to patient’s outcome, using a DNA pooling design. Methods: Patient’s outcome was assessed using the modified Rankin Scale (mRS) three months after stroke. Using the 250K Affymetrix GeneChip Mapping Assay® – Nsp I, we compared SNP allele frequencies in a pool of non-disabled stroke patients (N=87, mRS=0), with a pool of severely disabled or deceased patients (N=100, mRS>=3). The 100 most interesting SNPs were selected for validation by individual genotyping. Results: 36 SNPs were validated, showing significant differences between patients with extremely good and extremely poor outcome at three months (1.7x10-4 ).
- Novel and rare large deletions in the globin gene clusters causing different types of thalassemiaPublication . Coelho, Andreia; Fernandes, Emília; Batalha-Reis, Ana; Sonesson, Annika; Picanço, Isabel; Miranda, Armandina; Faustino, PaulaThe major component of the red blood cells is hemoglobin A which consists of 2α- and 2β-globin chains encoded by α- and β-globin genes located in two different gene clusters (16p13.3 and 11p.15.5, respectively). Molecular defects (usually point mutation or short deletion) that give rise to a quantitative reduction of the corresponding globin chain, result in a hereditary hypochromic and microcytic anemia called thalassemia. However, rarely, the molecular basis of the pathology could be a large deletion affecting several globin genes and/or their distal regulatory sequence. Four patients with hematological phenotypes suggestive of thalassemia, in whom no globinic molecular abnormalities had been found by standard diagnostic procedures, were screened for deletions in the telomeric region of chromosome 16 and 11, by Multiplex Ligation-dependent Probe Amplification (MLPA) assay. To further characterize the breakpoints of the deletions found, we employed synthetic MLPA probemixes designed in our laboratory, as well as PCR and DNA sequencing. We identified two cases of α-thalassemia caused by two distinct large deletions which remove all α-like structural genes and their distal regulatory sites: both are telomeric, one presents at least 271.14 kb of length and the other, at least, 231 kb. Concerning β-globin cluster screening, two deletions were found: one has at least 186 kb, encloses the entire cluster and its locus control region, and gives rise to a εγδβ0-thalassemia. The other presents at least 3 kb, has its 5’ breakpoint located within the second intron of the β-globin gene and its 3’ end within the L1 repetitive region of the cluster. Both α- and β-cluster larger deletions are novel and were named --CMB/αα and PORTUGUESE εγδβ0-Thal, respectively. The other two smaller deletions, given the uncertainty regarding their breakpoints, might be similar to others already published. In all patients, genotypes are well correlated with the different thalassemic phenotypes presented. MLPA proves to be a useful technique to identify known and unknown large deletions affecting globin gene clusters.
- Influence of LPL, APOAIV, APOAV, APOCIII and USF1 polymorphisms in a Portuguese population with clinical diagnosis of Familial Combined HyperlipidaemiaPublication . Santos, T.; Rato, Q.; Gaspar, I.M.; Bourbon, M.Familial Combined Hyperlipidaemia (FCHL) is a genetic disorder characterized by highly atherogenic profile with presence of sdLDL, hyperlipidaemia (hypertriglyceridaemia and/or hypercholesterolaemia), different lipid profiles in members of the same family and high apoB levels. Some polymorphisms in several genes (LPL -93T>G/D9N, APOAIV Q360H and V13M, APOAV -1131T>C and S19W, APOCIII 3238C>G, USF1s1 and USF1s2) have been associated with higher triglycerides (TG) levels or FCHL. Hypertriglyceridaemia has been suggested by some authors as an independent risk factor for cardiovascular diseases (CVD). The purpose of the present study was to verify if these associations are valid in a Portuguese FCHL population and if the above polymorphisms also affect sdLDL concentration since these particles are formed from triglyceride-rich VLDL (VLDL1). The molecular study of the above polymorphisms was performed in 45 FCHL index patients and 116 relatives by PCR amplification and direct sequencing. Total cholesterol (TC), TG, sdLDL and apoB values were measured in automated analysers. The results were analyzed with SPSS software using t-test. It was found at least one of the described polymorphism in 69 individuals (P1) but not in 92 (P2). We verified that individuals with at least one of these alterations had not only higher TG levels, as we were expecting, but also higher levels of sdLDL (TG: P1=186,1±11,0mg/dL, P2=136,7±7,3mg/dL, p<0,001; sdLDL: P1=33,2±2,3mg/dL, P2:22,6±2,2mg/dL, p=0,002). We didn’t found any significant relation between these polymorphisms and TC (P1=233,9±9,0mg/dL, P2=218,3±6,4, p=0,311). In P1 we also found an association between TG levels and CVD (with CVD: TG=227,5±23,4mg/dL, without CVD: TG=176,5±12,2mg/dL, p=0,036) that was not present in P2 (with CVD: TG=131,4±19,2mg/dL, without CVD: TG=137,3±7,9mg/dL, p=0,984). Our results not only reinforce the idea that hypertriglyceridaemia is a risk factor for CVD as suggested by some authors but also suggest that this condition is responsible for the increase of sdLDL particles in FCHL Portuguese patients.
- Biochemical and genetic evaluation of dyslipidemia in a population sample from São Brás de Alportel- AlgarvePublication . Francisco, Vânia; Barreto da Silva, Marta; Alves, Catarina; Rasteiro, Paula; Sousa, Eduardo; Vicente, A.M.; Gil, Ana PaulaDyslipidemia is an important cardiovascular risk factor and represent a serious public health problem in our society. The causes of dyslipidemia can be environmental, genetic or as a consequence of other conditions. The prevalence of this risk factor has not been determined in our population and a national epidemiologic study of prevalence of cardiovascular risk factors, is being conducted. In the scope of this project, a pilot study has been performed. Samples were collected in association with INSEF (Inquérito Nacional de Saúde com Exame Físico).