Browsing by Author "Santos, T."
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- Analysis of Genetic Markers for Cardiovascular Disorders in a Portuguese population with Familial HypercholesterolaemiaPublication . Gomes, A.; Santos, T.; Costa, L.; Bourbon, M.Familial Hypercholesterolaemia is a genetic disorder characterized by an increase in TC and LDLC leading to premature atherosclerosis (ATH) and cardiovascular disorders (CVD) but not all FH patients develops premature CVD. Early identification of FH patients at an even increased risk of developing CVD is important. Genetic markers could improve risk stratification for this patients. Inflammation has been considered to be involved in the pathogenesis of CVD and genetic and oxidative stress markers may also contribute to ATH and CVD outcome.
- Analysis of Genetic Markers for Cardiovascular Disorders in a Portuguese Population with Familial HypercholesterolaemiaPublication . Gomes, A.; Santos, T.; Costa, L.; Bourbon, M.Familial Hypercholesterolaemia (FH) is a genetic disorder that leads to an increase in levels of total and low density lipoprotein cholesterol promoting atherosclerosis (ATH) and premature cardiovascular disease (CVD). ATH and CVD are multifactorial disorders depending on both genetic and environmental factors and inflammation has been considered to be involved in the pathogenesis of ATH and CVD, namely the activity of pro-inflammatory cytokines and acute phase proteins. Also, there are other risk factors contributing to the development and progression of ATH and CVD as genetic and oxidative stress markers.
- Analysis of Genetic Markers for Cardiovascular Disorders in a Portuguese population with Familial HypercholesterolaemiaPublication . Gomes, A.; Santos, T.; Bourbon, M.Familial Hypercholesterolaemia (FH) is a genetic disorder leading to an increase in levels of total and low density lipoprotein cholesterol promoting atherosclerosis (ATH) and premature cardiovascular disease (CVD). Inflammation has been considered to be involved in the pathogenesis of CVD, namely the activity of pro-inflammatory cytokines and acute phase proteins. Genetic and oxidative stress markers may contribute to ATH and CVD outcome. We intended to investigate the role of genetic, inflammatory and oxidative biomarkers in the clinical outcome of FH patients and study its putative correlation with CVD. We selected 41 FH patients with CVD, 91 without CVD and 49 healthy individuals. All individuals were characterized through the determination of the lipid profile (high density lipoprotein, LDL and total cholesterol (TC), triglycerides (TG), apolipoproteinA, apolipoproteinB, lipoprotein(a)), measurement of serum concentration of inflammatory markers (ceruloplasmin, haptoglobin and C reactive protein), pro-inflammatory cytokines (interleukin-6 (IL6) and tumor necrosis factor-alpha (TNFα)), homocysteine and markers of antioxidant / pro-oxidant status (nitric oxid (NO) and oxidized LDL). Genetic characterization was achieved by the study of polymorphisms in the genes encoding for LPL, APOAV, APOCIII, TNF-α, IL6, MTHFR and NOS. The results showed that the group of FH patients with CVD presented increased TC (p<0,001) and LDL cholesterol (p=0,001) and apoB (p<0,001) levels and decreased apoA1 (p=0,021) levels in relation to the FH group without CVD. In the FH group with CVD it was observed the highest oxLDL and the lowest NO concentrations. APOAV-1131C and APOCIII 3238G allele were associated with higher TG levels (p=0,013; p=0,042) in the FH group without CVD. MTHFR 677T allele was associated with high TC levels (p=0,006) in the FH group with CVD. Markers of lipid metabolism are evident between the groups analyzed however inflammatory and genetic markers need further studies to improve our knowledge of their role in CVD outcome.
- Caracterização bioquímica e molecular de doentes com diagnóstico clínico de Dislipidemia Familiar CombinadaPublication . Santos, T.; Rato, Q.; Gaspar, I.M.; Guerra, A.; Rico, M.T.; Sequeira, S.; Silva, J.M.; Bourbon, M.A Dislipidemia Familiar Combinada (FCHL) é uma doença poligénica caracterizada por hiperlipidemia simples ou combinada, variabilidade intra-individual e intra-familiar do perfil lipídico, ApoB elevada (> 120 mg/dL) e risco elevado de doença cardiovascular (DCV). A sua causa é desconhecida mas alterações nos genes LPL, APOAIV, APOAV, APOCIII e USF1 parecem contribuir para o seu fenótipo. O objectivo deste estudo é caracterizar bioquímica e molecularmente doentes com diagnóstico clínico de FCHL. Todos os exões e promotor dos genes LPL, APOAIV, APOAV, APOCIII e regiões do gene USF1 (s1,s2) de 41 doentes foram amplificados por PCR e sequenciados. O colesterol total (CT), c-LDL, c-HDL, sdLDL, trigliceridos (TG), apoB e apoCIII foram determinados num aparelho automatizado. Em alguns doentes as sdLDL foram também analisadas por electroforese de lipoproteínas. A ApoAIV e ApoAV foram quantificadas por ELISA. Foram encontradas alterações genéticas em 37 doentes, 3 não descritas (APOAIV Q359_E362, APOAV D332fsX336 e APOCIII 3269C>A). O índex com a alteração Q359_E362del apresentou valores normais de apo AIV (15.5 mg/dL) e o índex com a alteração D332fsX336 apresentou valores baixos de apo AV (74.5 ng/mL). Os doentes estudados apresentam valores elevados de CT (285 ± 83 mg/dL), c-LDL (189 ± 85 mg/dL), TG (310 ± 253 mg/dL), e apo CIII (15 ± 4 mg/dL) e valores reduzidos de c-HDL (45 ± 11 mg/dL), sem medicação. Os valores de apoAIV (17,5 ± 10,4 mg/dL) e apoAV (150 ± 135 ng/mL) encontram-se, na maioria dos casos, no intervalo normal assim como os valores de sdLDL (35 ± 18 mg/dL), no entanto alguns casos apresentam valores acima do cut-off para DCV (35 mg/dL). A análise de sdLDL por electroforese foi realizada em 11 doentes, 9 dos quais apresentaram um perfil aterogénico. O valor médio de ApoB destes doentes era de 94 ± 43 mg/dL, mas aproximadamente 70% dos doentes estavam medicados com terapêutica hipolimiante (estatinas e/ou fibratos). Cerca de 30% dos doentes apresentavam DCV prematura. Os resultados obtidos parecem indicar que alterações nos genes estudados influenciam o fenótipo da FCHL. Os níveis séricos de apo CIII encontram-se alterados nesta dislipidemia. Doentes com FCHL, apesar de estarem medicados, apresentam valores elevados de sdLDL, evidenciando o seu elevado risco cardiovascular. A caracterização bioquímica complementa a identificação genética e permite uma melhor avaliação do risco cardiovascular do doente bem como a escolha de uma terapêutica adequada.
- Determination of sdLDL particles in patients with Familial Hyercholesterolaemia and Familial Combined HyperlipidaemiaPublication . Gomes, A.; Santos, T.; Bourbon, M.Several studies demonstrated that sdLDL are an emerging cardiovascular (CV) risk factor. The objective of this study was sdLDL measurement in patients with genetic diagnosis of Familial Hypercholesterolaemia (FH) and clinical diagnosis of Familial Combined Hyperlipidaemia (FCHL) to establish a relation between sdLDL, CV risk and the efficacy of therapeutics. Lipid profile was determined using a polyacrylamide gel electrophoresis system that separates the particles in serum that contain cholesterol. The lipidogram obtained classifies the patients as being profile A (low CV risk) or B (high CV risk) depending on the sdLDL concentration. The lipid profile was obtained from 43 FH adults and 46 FCHL adults, index and relatives. FH and FCHL patients without medication and with high sdLDL (>6mg/dl) have significant higher levels of total cholesterol, LDL and ApoB and FCHL patients also have significant higher triglycerides, compared to FH and FCHL patients with sdLDL levels under recommended values. Under medication FH patients have significant higher ApoB levels and lower HDL, and FCHL patients have significant higher total cholesterol, LDL and ApoB levels. Interestingly, 71,4% of FCHL patients under medication presented high CV risk profile, showing that statins seem not to decrease sdLDL levels and neither CV risk. Also FCHL patients are not well medicated or do not respond to usual medication to decrease cholesterol. These preliminary results indicate that sdLDL could be a good biomarker for treatment control but further studies are needed to evaluate the effect of medication in sdLDL levels in FH and FCHL patients.
- Extended characterization of lipidic profile: evaluation of lipoprotein subfractionsPublication . Leitão, F.; Berguete, S.; Santos, T.; Gomes, A.; Bourbon, M.Dyslipidaemia is one major cause for atherosclerosis and cardiovascular disease. Atherogenicity of LDL particles vary with particle size, density and lipid composition. Smaller and denser subparticles are more atherogenic than the larger ones, so it’s important to quantify and know the type of sdLDL present in an individual in order to access cardiovascular risk. The aim of this study is to compare and evaluate two different techniques for the analysis of the atherogenic lipidic profile of dyslipidaemic individuals.
- 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).
- Influence of APOE genotype in the phenotype of clinical diagnosed Portuguese FH patientsPublication . Medeiros, A.M.; Santos, T.; Alves, A.C.; Bourbon, M.APOE gene is polymorphic, comprises three frequent alleles (e2, e3, e4) which create six different genotypes and six protein isoforms with different affinity to LDLR. Isoform E2 has less affinity to receptor while isoform E4 have much efficient bond and compete with apoB. The present study pretends to evaluate the distribution of APOE alleles/genotype of index patients with clinical diagnosis of Familial Hypercholesterolemia (FH) and investigate if a specific allele/genotype is cause of hypercholesterolemia. APOE genotyping was performed using SnaPShot Multiplex System after PCR amplification. Biochemical parameters were determined by routine methods and results were analyzed with SPSS software using t- test. For this analysis, children and adults were divided according to their genetic diagnosis. Total of 353 patients were analyzed: 140 patients with mutation in LDLR, APOB or PCSK9 (44 children (G1), 96 adults (G2)) and 213 without a detectable mutation (70 children (G3), 143 adults (G4). Distribution of 6 genotypes (E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4) was as following: G1, 0%, 2.3%, 4.5%, 68.2%, 20.5%, 4.5%; G2, 1.0%, 1.0%, 4.2%, 62.5%, 28.1%, 3.1%; G3, 0%, 1.4%, 5.7%, 55.7%, 35.7%, 1.4%; G4, 0%, 1.4%, 5.6%, 63.5%, 25.9%, 3.5%. Statistical analysis revealed that presence of at least one e4 is associated with high levels of LDLc in G3/G4 patients (LDLcG3=182.96±49.46mg/dl, (e4/eX, X=2,3,4) vs LDLcG3=152.65±60.60mg/dl (eY/eZ, Y,Z=2,3), p=0.025; LDLcG4=227.69±43.17mg/dl, (e4/eX, X=2,3,4) vs LDLcG4=179.70±64.78mg/dl (eY/eZ, Y,Z=2,3), p<0.001)) but not in G1/G2 patients (p=0.100, p=0.832). Presence of e4 can be the cause of hypercholesterolemia presented by patients without genetic diagnosis of FH.
- 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.
- 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, Mafalda