Browsing by Author "Gaspar, I.M."
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- 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.
- Familial hypercholesterolaemia: a global call to armsPublication . Vallejo-Vaz, A.J.; Kondapally Seshasai, S.R.; Cole, D.; Hovingh, G.K.; Kastelein, J.J.; Mata, P.; Raal, F.J.; Santos, R.D.; Soran, H.; Watts, G.F.; Abifadel, M.; Aguilar-Salinas, C.A.; Akram, A.; Alnouri, F.; Alonso, R.; Al-Rasadi, K.; Banach, M.; Bogsrud, M.P.; Bourbon, M.; Bruckert, E.; Car, J.; Corral, P.; Descamps, O.; Dieplinger, H.; Durst, R.; Freiberger, T.; Gaspar, I.M.; Genest, J.; Harada-Shiba, M.; Jiang, L.; Kayikcioglu, M.; Lam, C.S.; Latkovskis, G.; Laufs, U.; Liberopoulos, E.; Nilsson, L.; Nordestgaard, B.G.; O'Donoghue, J.M.; Sahebkar, A.; Schunkert, H.; Shehab, A.; Stoll, M.; Su, TC; Susekov, A.; Widén, E.; Catapano, A.L.; Ray, K.K.Familial Hypercholesterolaemia (FH) is the commonest autosomal co-dominantly inherited condition affecting man. It is caused by mutation in one of three genes, encoding the low-density lipoprotein (LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene coding for PCSK9 (which is involved in the degradation of the LDLreceptor during its cellular recycling). These mutations result in impaired LDL metabolism, leading to life-long elevations in LDLcholesterol (LDL-C) and development of premature atherosclerotic cardiovascular disease (ASCVD) [1e3]. If left untreated, the relative risk of premature coronary artery disease is significantly higher in heterozygous patients than unaffected individuals, with most untreated homozygotes developing ASCVD before the age of 20 and generally not surviving past 30 years [2e5]. Although early detection and treatment with statins and other LDL-C lowering therapies can improve survival, FH remains widely underdiagnosed and undertreated, thereby representing a major global public health challenge.
- 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
- Molecular diagnosis of familial hypercholesterolemia: an important tool for cardiovascular risk stratificationPublication . Alves, A.C.; Medeiros, A.M.; Francisco, V.; Gaspar, I.M.; Rato, Q.; Bourbon, M.Familial hypercholesterolemia (FH) is associated with an increased risk of premature coronary heart disease. Molecular identification of these patients can reduce the burden of mortality from cardiovascular disorders simply by the correct identification of the disease early in life, followed by counseling and appropriate lifestyle modifications, and therapeutic measures when required. Recent studies show that, in Portugal, this disease is severely under-diagnosed. After more than 10 years of research through the Portuguese FH Study, it is now possible to translate the original research results into clinical application. AIMS: The main aims of the present work were to determine whether clinical characterization is sufficient to identify these individuals at high risk of developing CHD and to evaluate the clinical applicability of molecular diagnosis for FH. METHODS: All patients described in this study were recruited for the Portuguese FH Study. The diagnostic criteria used to select the index patients were adapted from the Simon Broome Heart Research Trust. To analyze the usefulness of the molecular diagnosis, graphs of total and LDL cholesterol values by age were constructed for 622 possible FH patients. The lipid profile of patients genetically identified as having FH, before and under medication, were analyzed to assess whether these patients were receiving appropriate treatment. The data are shown separately for children and adults and for female and male propositi (index cases and hypercholesterolemic relatives), both with and without a detectable mutation in the LDLR gene. RESULTS: The Portuguese FH Study has already genetically identified 404 individuals (171 index patients and 233 relatives) among more than one thousand individuals sent for study. A total of 78 different mutations in the LDLR gene were found in 171 index patients, 2 different mutations were found in the apoB gene of 4 patients and 2 patients had a unique PCSK9 mutation. Statistical analysis revealed that there are significant differences between total cholesterol (p < 0.001) and apoB (p = 0.026) values in the group of children (male and female) with and without a mutation in LDLR. For female children LDL values were also significantly different (p < 0.001) between subgroups but for male children this difference did not reach statistical significance. In adult women there is a statistically significant difference for total cholesterol (p = 0.049), LDL cholesterol (p = 0.031) and apoB (p = 0.003) values in the subgroups with and without a LDLR mutation. In adult males there is a statistical difference for total cholesterol (p = 0.002). LDL cholesterol (p = 0.003) and apoB (p = 0.0023) in subgroups with and without an LDLR mutation. Nevertheless there was considerable dispersion of values and individually it is not possible to distinguish between patients with and without a mutation in the LDLR gene, based only on lipid profile. CONCLUSIONS: By analysis of the clinical data of 696 possible FH patients, the present report shows evidence that clinical characterization is not sufficient to distinguish between patients with genetic or environmental dyslipidemia, and so molecular diagnosis is useful in clinical practice, allowing correct identification of FH patients and their relatives, and the early implementation of therapeutic measures to reduce the elevated cardiovascular risk of these patients. In general, molecular diagnosis of FH is feasible and could be obtained in 1-2 months if the technology is available. In Portugal the test will be offered to the population by our Institute at a cost of about 500 euros, like many other genetic tests or exams such as nuclear magnetic resonance.
- Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies CollaborationPublication . EAS Familial Hypercholesterolaemia Studies Collaboration; Vallejo-Vaz, A.J.; Akram, A.; Kondapally Seshasai, S.R.; Cole, D.; Watts, G.F.; Hovingh, G.K.; Kastelein, J.J.; Mata, P.; Raal, F.J.; Santos, R.D.; Soran, H.; Freiberger, T.; Abifadel, M.; Aguilar-Salinas, C.A.; Alnouri, F.; Alonso, R.; Al-Rasadi, K.; Banach, M.; Bogsrud, M.P.; Bourbon, M.; Bruckert, E.; Car, J.; Ceska, R.; Corral, P.; Descamps, O.; Dieplinger, H.; Do, C.T.; Durst, R.; Ezhov, M.V.; Fras, Z.; Gaita, D.; Gaspar, I.M.; Genest, J.; Harada-Shiba, M.; Jiang, L.; Kayikcioglu, M.; Lam, C.S.; Latkovskis, G.; Laufs, U.; Liberopoulos, E.; Lin, J.; Lin, N.; Maher, V.; Majano, N.; Marais, A.D.; März, W.; Mirrakhimov, E.; Miserez, A.R.; Mitchenko, O.; Nawawi, H.; Nilsson, L.; Nordestgaard, B.G.; Paragh, G.; Petrulioniene, Z.; Pojskic, B.; Reiner, Ž.; Sahebkar, A.; Santos, L.E.; Schunkert, H.; Shehab, A.; Slimane, M.N.; Stoll, M.; Su, T.C.; Susekov, A.; Tilney, M.; Tomlinson, B.; Tselepis, A.D.; Vohnout, B.; Widén, E.; Yamashita, S.; Catapano, A.L.; Ray, K.K.BACKGROUND: The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. METHODS: The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. CONCLUSIONS: The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients.
- Relation between triglycerides associated polymorphisms and lipid profile in 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 prevalence of sdLDL particles, hyperlipidaemia (hypertriglyceridaemia and/or hypercholesterolaemia) and high apoB levels (>120 mg/dL), with different lipid profiles in members of the same family. 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 levels of triglycerides (TG) or FCHL. Hypertriglyceridaemia (HTG) has also been suggested by some authors as an independent risk factor for cardiovascular diseases (CVD).
- Update of the biochemical and molecular results of Portuguese patients with Familial Combined HyperlipidaemiaPublication . Santos, T.; Rato, Q.; Gaspar, I.M.; Rico, M.T.; Silva, J.M.; Bourbon, M.FCHL is a complex disorder with a highly atherogenic profile. The aim of this study is the biochemical/molecular characterization of FCHL patients. Molecular study of LPL, APOAIV, APOAV, APOCIII and USF1 (s1,s2) was performed in 35 index patients by PCR amplification and sequencing. Total cholesterol (TC), HDL-c, sdLDL, triglycerides (TG), apoB and apoCIII were measured in automated analysers. sdLDL was also analysed by electrophoresis with Lipoprint®. ApoAIV and ApoAV were measured by ELISA. For all patients, biochemical characterization of apolipoproteins and sdLDL before treatment was not possible to determine. Prior to medication the levels of TC (305±62mg/dL) and TG (380±269mg/dL) were high but HDL-c was normal (44±11mg/dL). Even under medication these patients presented high levels of CT (205±58mg/dL), TG (233±109mg/dL) and ApoCIII (15±4mg/dL) and normal levels of HDL-c (44±9mg/dL). ApoAIV (17±10mg/dL), ApoAV (156±140ng/mL) and ApoB (89±41mg/dL) levels were within normal range in majority of cases. Lipoprint® analysis of 8 patients under medication revealed an atherogenic pattern. Two new alterations were found. One patient with TC=271mg/dl and TG=275mg/dL carried APOAIV Q359_E362 (values without medication). Another patient with TC=419mg/dL and TG=1095mg/dL presented APOAV D332fsX336 and, even under medication, had high sdLDL (39 mg/dL, cut-off value 35mg/dl) and an atherogenic pattern with Lipoprint® analysis (pattern B). Some patients had a novel alteration APOCIII 3269C>A that was proven later that was a polymorphism. Patients with FCHL have increased cardiovascular risk that can be prevented with an early genetic identification and an extensive biochemical characterization that can be important to evaluate the efficacy of treatment.