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2.
Arq. bras. cardiol ; 116(4): 706-712, abr. 2021. tab, graf
Article in Portuguese | LILACS | ID: biblio-1285185

ABSTRACT

Resumo Fundamento Indivíduos com hipercolesterolemia grave apresentam alto risco de desenvolver doença cardiovascular aterosclerótica (DCVA). Muitos deles apresentam hipercolesterolemia familiar (HF). Objetivos Avaliar, a partir da perspectiva dos pacientes, o nível de conhecimento sobre a hipercolesterolemia grave, especialmente em relação a HF, DCVA, percepção de risco, desempenho do rastreamento em cascata e tratamento de indivíduos participantes de um programa de avaliação periódica de saúde. Métodos De um banco de dados de 70.000 brasileiros avaliados entre 2006 e 2016, 1.987 (2,8%) atenderam aos critérios de inclusão (idade ≥ 18 anos e LDL-C ≥ 190 mg/dL ou ≥ 160 mg/dL se sem uso de estatinas ou em terapia com estatinas, respectivamente). Desses, 200 foram aleatoriamente convidados a preencher um questionário extenso. A HF foi diagnosticada em caso de suspeita pelo médico responsável. Resultados Embora 97% da amostra (48±9 anos; 16% do sexo feminino; 95% com ensino superior; 88% em prevenção primária; LDL-C 209±47 mg/dL) tenha apresentado hipercolesterolemia grave, apenas 18% e 29,5% se consideravam de alto risco para desenvolver DCVA e relataram saber sua meta recomendada de LDL-C, respectivamente. Em relação à possibilidade de o colesterol alto ser uma doença hereditária, 58% relataram conhecimento sobre o fato; 24,5% (n = 49) já tinham ouvido falar em HF; e apenas 14% (n = 20) foram previamente identificados com suspeita de HF (idade ao diagnóstico de HF: 35±12 anos; 79% e 31% foram diagnosticados com > 30 e > 40 anos, respectivamente). Apenas 2,5% foram submetidos a testes genéticos; 17%, à rastreamento em cascata; e 17% não faziam uso de tratamento farmacológico. Conclusões Identificou-se uma importante lacuna na percepção de risco, no controle do colesterol e em aspectos relacionados à HF em indivíduos com hipercolesterolemia grave. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)


Abstract Background Individuals with severe hypercholesterolemia are at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). Many of them have familial hypercholesterolemia (FH). Objectives To assess from a patient perspective the degree of awareness about severe hypercholesterolemia, especially FH, ASCVD risk perception, cascade screening performance, and treatment of individuals participating in a routine health evaluation program. Methods From a database of 70,000 Brazilian individuals evaluated between 2006 and 2016, 1,987 (2.8%) met the inclusion criteria (age ≥ 18 years and LDL-C ≥ 190 mg/dL or ≥ 160 mg/dL, respectively, if not in use of statins or on statin therapy). Two-hundred individuals were randomly invited to complete an extensive questionnaire. FH was diagnosed if suspected by the attending physician. Results Although 97% of the sample (age 48±9 years; 16% women; 95% college/university education; 88% primary prevention; LDL-C 209±47 mg/dL) had severe hypercholesterolemia, only 18% and 29.5% believed to be at high ASCVD risk and reported knowledge of their recommended LDL-C goal, respectively. Fifty-eight percent reported being informed that high cholesterol could be a family disease, 24.5% (n = 49) had ever heard about FH, and merely 14% (n = 29) had been previously identified as suspected of having FH (age at FH diagnosis 35±12 years; 79% and 31% diagnosed, respectively, > 30 and > 40 years old). Only 2.5% underwent genetic tests, 17% underwent cascade screening, and 17% were not in use of pharmacological treatment. Conclusions An important gap in risk perception, cholesterol management, and aspects related to FH was encountered in individuals with severe hypercholesterolemia. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)


Subject(s)
Humans , Male , Female , Adolescent , Adult , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Hypercholesterolemia/drug therapy , Hyperlipoproteinemia Type II/drug therapy , Brazil , Risk Factors , Heart Disease Risk Factors , Cholesterol, LDL , Middle Aged
3.
J. bras. econ. saúde (Impr.) ; 13(1): 14-20, Abril/2021.
Article in English | LILACS, ECOS | ID: biblio-1252666

ABSTRACT

Objective: Familial hypercholesterolaemia is a hereditary disease characterized by very high levels of low-density lipoprotein cholesterol and an elevated risk of early-onset cardiovascular disorders. New drugs provide alternatives for the treatment of patients with homozygous familial hypercholesterolaemia. The study aims to explore a practical application of multiple-criteria decision analysis on prioritization of new and emerging technologies for familial hypercholesterolaemia. Methods: The decision model was constructed using the MACBETH method. There were three stages: structuring the problem, measuring the performance of alternatives, and building the model. The weights for alternatives and levels were obtained by indirect comparisons, which evaluated the attractiveness of the performance levels of the criteria using the swing weights technique. Results: The drugs lomitapide, ezetimibe, evolocumab, and mipomersen were selected as alternatives for decision-making. "Cardiovascular Death", "Stroke" and "Acute Myocardial Infarction" had the three most significant weights. The criteria with the lowest weights were "Comfort" and "LDL-C Reduction". The top-ranked technology was evolocumab, with an overall score of 59.87, followed by ezetimibe, with a score of 37.21. Conclusion: How to apply the result of a higher score in the actual decisionmaking process still requires further studies. The case in question showed that evolocumab has more performance benefits than other drugs but with a cost approximately 50 times higher


Objetivo: A hipercolesterolemia familiar é uma doença hereditária caracterizada por níveis muito elevados de lipoproteína de baixa densidade (LDL-colesterol) e um risco elevado de doenças cardiovasculares de início precoce. Novos medicamentos oferecem alternativas para o tratamento de pacientes com hipercolesterolemia familiar homozigótica. Esse estudo tem como objetivo explorar uma aplicação prática da análise de decisão multicritério na priorização de tecnologias novas e emergentes para hipercolesterolemia familiar. Métodos: O modelo de decisão foi construído usando o método MACBETH. Três etapas foram criadas: estruturação do problema, mensuração do desempenho das alternativas e construção do modelo. Os pesos para alternativas e níveis foram obtidos por comparações indiretas, que avaliaram a atratividade dos níveis de desempenho dos critérios usando a técnica de pesos de balanço. Resultados: Os medicamentos lomitapida, ezetimiba, evolocumabe e mipomersen foram selecionados como alternativas para a tomada de decisão. "Morte Cardiovascular", "Acidente vascular cerebral" e "Infarto Agudo do Miocárdio" tiveram os três pesos mais significativos. Os critérios com os menores pesos foram "Conforto" e "Redução do LDL-C". A tecnologia mais bem avaliada foi o evolocumabe, com pontuação geral de 59,87, seguido da ezetimiba, com pontuação de 37,21. Conclusão: Ainda são necessários estudos para determinar como aplicar o resultado de uma pontuação mais alta no processo de tomada de decisão. O caso em questão demonstrou que o evolocumabe tem benefícios mais significativos em relação aos outros medicamentos, mas com um custo cerca de 50 vezes maior


Subject(s)
Technology Assessment, Biomedical , Decision Making , Hyperlipoproteinemia Type II
4.
Rev. colomb. cardiol ; 27(6): 501-510, nov.-dic. 2020. tab, graf
Article in Spanish | LILACS | ID: biblio-1289265

ABSTRACT

Resumen Introducción: La hipercolesterolemia familiar homocigótica (HFHo) se caracteriza por niveles muy elevados de cLDL y por enfermedad aterosclerótica temprana. Aunque la frecuencia es baja (1/300.000), las complicaciones son muy severas y pueden ser evitadas. Encontrar y tratar esta población de manera temprana podría reducir la mortalidad. Se describen 36 casos en Colombia, en donde se calcula que haya entre 160 y 200 casos. Resultados: Un total de 36 pacientes con fenotipo sugestivo de HFHo fueron identificados y tratados en un período de observación de cuatro años. La media de edad fue 27 años (24 mujeres). 34 pacientes tuvieron un puntaje según la Red de Clínicas de Lípidos de Holanda (RCLH) mayor de 8 (diagnóstico definitivo) y los restantes 2 tenían puntaje equivalente a diagnóstico probable. Un cuarto de los casos procedían de la costa norte colombiana. En las pruebas genéticas, 14 fueron homocigóticos verdaderos para mutación del gen que codifica para el receptor de LDL (LDLR), 12 heterocigóticos compuestos, 2 heterocigóticos dobles y uno autosómico recesivo (LDLRAP1); 5 pacientes fueron heterocigóticos simples (LDLR) y 2 pacientes no autorizaron la prueba. En los homocigóticos verdaderos, la variante más frecuente encontrada fue la c.11G>A. 14 pacientes cursaron con enfermedad coronaria, 9 con estenosis carotídea, 8 con estenosis aórtica y 2 tuvieron ataques cerebrovasculares (ACV). 34 pacientes recibían estatinas (24 rosuvastatina), 30 recibían ezetimibe, 2 recibían evolocumab y 20 recibían lomitapide (dosis promedio 12,7mg). Ninguno recibió aféresis de cLDL. Los medicamentos, en general, fueron bien tolerados y la reducción promedio de cLDL con la terapia fue de 533,7mg/dl a 245,1mg/dl (54%). Conclusiones: Todos los pacientes recibieron tratamiento hipolipemiante y se encontraron alteraciones genéticas diagnósticas en todos aquellos que autorizaron el examen. Los niveles elevados de cLDL conllevan tanto riesgo que el tratamiento debe establecerse aún sin conocer el diagnóstico genético.


Abstract Background: Homozygous familial hypercholesterolemia (HoFH) is characterized for very high levels of cLDL and early cardiovascular disease. Although incidence is low (1/300 000), complications are very severe and can be avoided. Finding and treating this population promptly could reduce mortality. We describe 36 cases in Colombia, where 160 to 200 cases are expected. Results: 36 patients with phenotype of HoHF were identified and treated in a follow-up of 4 years. The mean age was 27 years (24 women). 34 of them had at least 8 points in the FH Dutch Lipid Clinic Criteria (definitive diagnosis) and two had probable diagnosis. A quarter of the cases came from the Colombian North Coast. In molecular tests, 14 were true homozygous for LDLR, 12 were compound heterozygous for LDLR, 2 double heterozygous and one was autosomal recessive; 5 were heterozygous and 2 patients did not authorized genetic test. In true homozygous subjects, the most frequent variant was c.11G>A. 14 patients had coronary disease, 9 carotid stenosis, 8 aortic stenosis and 2 had stroke. 34 patients were on statins (25 rosuvastatin), 30 were receiving ezetimibe, 2 were receiving a PSCK9 inhibitor (evolocumab) and 20 were on lomitapide with mean doses of 12.7mg. None received lipoprotein apheresis. Medications were very well tolerated. Changes in cLDL after therapy was from 533.7 mg/dL to 245 mg/dL, (54%). Conclusions: Treatment was started in all patients. We found genetic mutations in all patients with genetic tests. The high levels of cLDL mean such a high risk that treatment must be started promptly, even without a genetic test.


Subject(s)
Humans , Male , Female , Adult , Hypercholesterolemia , Alleles , Genetics , Hyperlipoproteinemia Type II , Lipids , Cholesterol, LDL , Mutation
5.
Arq. bras. cardiol ; 115(3): 587-589, out. 2020.
Article in English, Portuguese | SES-SP, LILACS, SES-SP | ID: biblio-1131306

ABSTRACT

Resumo A hipercolesterolemia familiar (HF) é uma doença genética causada por um defeito primário no gene que codifica o receptor da LDL. Mutações diferentes no mesmo gene caracterizam um heterozigoto composto, mas pouco se sabe sobre o fenótipo dos portadores. Portanto, neste estudo, descrevemos o rastreamento em cascata de uma família brasileira com essa característica. O caso-índice é um homem de 36 anos, com colesterol total (CT) de 360 mg/dL (9,3 mmol/L) e concentração de LDL-c de 259 mg/dL (6,7 mmol/L), além de xantomas de tendão de Aquiles, obesidade e pré-hipertensão. A genotipagem identificou as mutações 661G>A, 670G>A e 682G>A, no exon 4, e 919G>A, no exon 6. A mesma mutação no exon 4 foi observada no filho do caso-índice (7 anos), que também tem hipercolesterolemia e xantomas tendinosos, ao passo que a filha do caso-índice (9 anos) apresenta mutação no exon 6 e hiperlipidemia, sem xantomas. Em suma, este relato permite uma melhor compreensão acerca da base molecular da HF no Brasil, um país multirracial, onde é esperada uma população heterogênea.


Abstract Familial hypercholesterolemia (FH) is a genetic disease caused by a primary defect in the LDL-receptor gene. Distinct variants in the same gene characterize a compound heterozygote, but little is known about the phenotypes of the carriers. Therefore, herein, we describe the cascade screening of a Brazilian family with this characteristic. The index case, a 36-year-old male, had a total cholesterol level of 360 mg/dL (9.3 mmol/L) and LDL-c value of 259 mg/dL (6.7 mmol/L), in addition to Achilles tendon xanthomas, obesity and prehypertension. Genotyping identified the variants 661G>A, 670G>A, 682G>A in exon 4 and 919G>A in exon 6. The same variant in exon 4 was found in the index case's son (7-y), who also had hypercholesterolemia and xanthomas, while the index case's daughter (9-y) had the variant in exon 6 and hyperlipidemia, without xanthomas. In summary, this report allows for a better insight into the molecular basis of FH in Brazil, a multi-racial country where a heterogeneous population is expected.


Subject(s)
Humans , Male , Adult , Hyperlipoproteinemia Type II/genetics , Phenotype , Brazil , Receptors, LDL/genetics , Heterozygote
6.
Rev. chil. nutr ; 47(5): 757-764, set. 2020. tab
Article in English | LILACS | ID: biblio-1138612

ABSTRACT

ABSTRACT The study aims to evaluate the association between inadequate consumption of antioxidant minerals and plasma lipoprotein concentrations in adolescents. We conducted a cross-sectional study that evaluated sociodemographic and anthropometric data, information on intake of magnesium, selenium and zinc and lipid profile. Student's t-test was used to compare means between the groups and logistic regression to verify the strength of the association between the independent variables and lipid profile. Inadequate zinc consumption was associated with a higher chance of low HDL-c levels and lower chance of hypertriglyceridemia and high LDL-c levels. Inadequate selenium intake was associated with a lower chance of high total cholesterol and of high triglyceride concentrations and a higher chance of low HDL-c levels. Inadequate magnesium consumption was associated with a higher chance of high cholesterol and triglyceride levels, a lower chance of high LDL-c levels and with a higher chance of low HDL-c. We observed an association between inadequate consumption of magnesium, zinc and selenium and changes in the lipid profile of adolescents.


RESUMEN El estudio tiene como objetivo evaluar la asociación entre el consumo inadecuado de minerales antioxidantes y las concentraciones plasmáticas de lipoproteínas en adolescentes. Estudio transversal que evaluó datos sociodemográficos y antropométricos, información sobre ingesta de magnesiom selenio y zinc y perfil lipídico. Se utilizó la prueba t de Student para comparar medias entre los grupos y regresión logística para verificar la fuerza de la asociación entre las variables independientes y el perfil lipídico. El consumo inadecuado de zinc se asoció con una mayor probabilidad de niveles bajos de HDL-c y una menor probabilidad de hipertrigliceridemia y niveles altos de LDL-c. La ingesta inadecuada de selenio se asoció con una menor probabilidad de colesterol total alto y de altas concentraciones de triglicéridos y una mayor probabilidad de niveles bajos de HDL-c. El consumo inadecuado de magnesio se asoció con una mayor probabilidad de niveles altos de colesterol y triglicéridos, una menor probabilidad de niveles altos de LDL-c y una mayor probabilidad de niveles bajos de HDL-c. El estudio muestra una asociación entre el consumo inadecuado de magnesio, zinc y selenio y los cambios en el perfil lipídico de los adolescentes.


Subject(s)
Adolescent , Selenium , Zinc , Magnesium , Minerals , Dyslipidemias , Heart Disease Risk Factors , Hyperlipoproteinemia Type II
7.
Arch. cardiol. Méx ; 90(2): 130-136, Apr.-Jun. 2020. tab, graf
Article in English | LILACS | ID: biblio-1131021

ABSTRACT

Abstract Objective: Familial hypercholesterolemia (FH) is a monogenic disease, associated with variants in the LDLR, APOB and PCSK9 genes. The initial diagnosis is based on clinical criteria like the DLCN criteria. A score > 8 points qualifies the patient as "definite" for FH diagnosis. The detection of the presence of a variant in these genes allows carrying out familial cascade screening and better characterizes the patient in terms of prognosis and treatment. Methods: In the context of the FH detection program in Argentina (Da Vinci Study) 246 hypercholesterolemic patients were evaluated, 21 with DLCN score > 8 (definite diagnosis).These patients were studied with next generation sequencing to detect genetic variants, with an extended panel of 23 genes; also they were adding the large rearrangements analysis and a polygenic score of 10 SNP (single nucleotide polymorphism) related to the increase in LDL-c. Results: Of the 21 patients, 10 had variants in LDLR, 1 in APOB with APOE, 1 in LIPC plus elevated polygenic score, and 2 patients showed one deletion and one duplication in LDLR, the later with a variation in LIPA. It is highlighted that 6 of the 21 patients with a score > 8 did not show any genetic alteration. Conclusions: We can conclude that 28% of the patients with definite clinical diagnosis of FH did not show genetic alteration. The possible explanations for this result would be the presence of mutations in new genes, confusing effects of the environment over the genes, the gene-gene interactions, and finally the impossibility of detecting variants with the current available methods.


Resumen Objetivo: La hipercolesterolemia familiar (HF) es una enfermedad monogénica asociada a variantes en los genes RLDL, APOB y PCSK9. El diagnóstico inicial se basa en criterios clínicos, como el de la red de clínica de lípidos holandesa (DLCN). Un puntaje > 8 puntos califica al paciente como "definitivo" para diagnóstico de HF. La identificación de una variante en estos genes permite realizar el cribado en cascada familiar y caracterizar mejor al paciente en cuanto al pronóstico y el tratamiento. Métodos: En el marco del Programa de Detección de HF en Argentina (Estudio Da Vinci) se evaluó a 246 pacientes hipercolesterolémicos, 21 con puntaje DLCN > 8 (diagnóstico definitivo). Se estudió a estos pacientes con secuenciación de próxima generación para reconocer variantes genéticas, con un panel ampliado de 23 genes, sumado al análisis de grandes rearreglos y por último se aplicó un score poligénico de 10 SNP (polimorfismo de nucleótido único) relacionados con aumento del c-LDL. Resultados: De los 21 pacientes, 10 presentaron variantes en RLDL, uno en APOB junto a APOE, uno en LIPC más puntaje poligénico elevado, dos pacientes con una deleción y una duplicación en RLDL y este último caso con una variante en LIPA. Es destacable que 6 de los 21 pacientes con puntaje DLCN > 8 no mostraron ninguna alteración genética. Conclusiones: El 28% de los pacientes con diagnóstico clínico definitivo de HF no evidenció alteración genética. Las posibles explicaciones de este resultado serían la presencia de mutaciones en nuevos genes, los efectos confundidores del ambiente sobre los genes o la interacción gen-gen y por último la imposibilidad de detectar variantes con la metodología actual disponible.


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Receptors, LDL/genetics , Apolipoprotein B-100/genetics , Proprotein Convertase 9/genetics , Hyperlipoproteinemia Type II/genetics , Apolipoproteins E/genetics , Phenotype , Argentina , Genetic Variation , Polymorphism, Single Nucleotide , Mutation
9.
Rev. Assoc. Med. Bras. (1992) ; 66(1): 31-35, Jan. 2020. tab, graf
Article in English | LILACS | ID: biblio-1091903

ABSTRACT

SUMMARY Homozygous familial hypercholesterolemia is a rarely agentic disorder of the lipoprotein metabolism intimately related to premature atherosclerotic cardiovascular disease that can lead to high disability and mortality. Homozygous familial hypercholesterolemia typically affects not only the aortic root, compromising the coronary ostia, but also affects other territories such as the carotid, descending aorta, and renal arteries. Multi-contrast high-resolution magnetic resonance imaging (MRI) provides a validated and useful method to characterize carotid artery atherosclerotic plaques quantitatively. However, very few studies have been done on assessing plaque composition in patients with Homozygous familial hypercholesterolemia using high-resolution MRI. This report is to evaluate the value of MRI in accessing carotid artery disease in patients with Homozygous familial hypercholesterolemia. We describe a 28-year-old patient from Beijing, China, who presented to the Neurology Clinic with intermittent blurred vision of the right eye, headache, nausea, and vomiting for eight years without obvious causes. Familial hypercholesterolemia was suspected based on medical history and laboratory examination. Carotid Doppler ultrasound showed bilateral common carotid artery, internal carotid artery, and external carotid artery wall thickening with hyperechoic signals. Subsequently, high-resolution multi-contrast MRI of the carotid showed calcification with hypo-intense areas located at the middle layer of the plaque, with moderate stenosis. The plaque located at the right bifurcation of the common carotid artery extended to the internal carotid artery, causing lumen stenosis close to occlusion. The patient was treated with right carotid artery endarterectomy. At a 6-month follow-up, there had been no recurrence of the patient's symptoms.


RESUMO A hipercolesterolemia familiar homozigótica, uma doença patogênica rara do metabolismo da lipoproteína intimamente relacionada com a doença cardiovascular aterosclerótica prematura, pode conduzir a uma elevada deficiência e mortalidade. A hipercolesterolemia familiar homozigótica afeta tipicamente não só a raiz aórtica, comprometendo os óstios coronários, mas também outros territórios, como a carótida, a aorta descendente e as artérias renais. Imagens de ressonância magnética multicontraste de alta resolução (RM) fornecem um método validado e útil para caracterizar quantitativamente as placas de aterosclerose da artéria carótida. No entanto, muito poucos estudos foram feitos sobre a avaliação da composição da placa em doentes com hipercolesterolemia familiar homozigótica utilizando ressonância magnética de alta resolução. Este trabalho deve avaliar o valor da ressonância magnética no acesso à doença da artéria carótida em doentes com hipercolesterolemia familiar homozigótica. Descrevemos um paciente de 28 anos de Pequim, China, que se apresentou à clínica neurológica com visão turva intermitente do olho direito, dor de cabeça, náuseas e vômitos por oito anos sem causas aparentes. Suspeitava-se de hipercolesterolemia familiar com base no histórico médico e no exame laboratorial. O ultrassom Doppler carotídeo mostrou uma artéria carótida bilateral comum, artéria carótida interna e parede da carótida externa espessando-se com sinais hiperecoicos. Posteriormente, a ressonância multicontraste de alta resolução da carótida mostrou calcificação com áreas hipointensas localizadas na camada média da placa, com estenose moderada. A placa localizada na bifurcação direita da artéria carótida comum estendia-se até a artéria carótida interna, causando estenose do lúmen próxima à oclusão. O paciente foi tratado com endarterectomia da artéria carótida direita. Em seis meses de acompanhamento, não houve recorrência dos sintomas do paciente.


Subject(s)
Humans , Female , Adult , Thrombosis/diagnostic imaging , Coronary Artery Disease/diagnostic imaging , Magnetic Resonance Imaging/methods , Carotid Stenosis/diagnostic imaging , Plaque, Atherosclerotic/diagnostic imaging , Hyperlipoproteinemia Type II/diagnostic imaging , Carotid Artery, External/pathology , Carotid Artery, External/diagnostic imaging , Carotid Artery, Internal/pathology , Carotid Artery, Internal/diagnostic imaging , Ultrasonography, Doppler, Color/methods , Plaque, Atherosclerotic/pathology , Carotid Intima-Media Thickness , Computed Tomography Angiography/methods
10.
Article in English | WPRIM | ID: wpr-811204

ABSTRACT

Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder that presents as abnormally elevated levels of low-density lipoprotein cholesterol and premature heart disease, requiring frequent intervention through lipid apheresis for management. The risk of perioperative cardiac events is higher in patients with HoFH because of its pathophysiological manifestations in the vascular system. Careful cardiac precautions and anesthetic assessments are necessary to ensure patient safety. In the following case report, we discuss the clinical course and anesthetic considerations for a 14-year-old girl with HoFH undergoing sedation for dental extractions and mandibular molar uprighting in an outpatient oral surgery clinic. Considerations included the use of heparin in the patient's weekly plasma lipid apheresis treatment. In order to reduce the risks of peri- and postoperative bleeding and perioperative cardiac events, the operation was scheduled for 4 days after apheresis. This allowed for adequate heparin clearance, while also reducing the likelihood of possible cardiac events. A literature review revealed no results for the outpatient management of patients with HoFH undergoing sedation for noncardiac procedures. Our reported case serves as a clinical example for physicians to be utilized in the future.


Subject(s)
Adolescent , Anesthesia, Dental , Blood Component Removal , Cholesterol , Female , Heart Diseases , Hemorrhage , Heparin , Humans , Hyperlipoproteinemia Type II , Lipoproteins , Molar , Outpatients , Patient Safety , Plasma , Surgery, Oral
11.
Med. infant ; 26(3): 287-295, sept. 2019. Tab, ilus
Article in Spanish | LILACS | ID: biblio-1025029

ABSTRACT

La Hipercolesterolemia Familiar (HF) es una enfermedad hereditaria frecuente que se caracteriza por niveles elevados de colesterol ligado a las lipoproteínas de baja densidad (C-LDL). El exceso de LDL se acumula en las arterias produciendo aterosclerosis prematura. El diagnóstico y tratamiento desde la infancia mejoran el pronóstico de la enfermedad. Existe subdiagnóstico de la HF lo que provoca muertes prematuras por enfermedad cardiovascular (ECV). Para mejorar el subdiagnóstico la Sociedad Argentina de Pediatría propuso en el año 2015 realizar tamizaje universal al ingreso escolar. Es relevante entonces que el pediatra pueda diagnosticar la hipercolesterolemia y diferenciar las hipercolesterolemias monogénicas o familiares, de las secundarias (AU)


Familial hypercholesterolemia (FH) is a common hereditary disease that is characterized by high cholesterol levels, linked to low-density lipoproteins (LDL). Excess LDL accumulates in the arteries leading to premature atherosclerosis. Early diagnosis and treatment since childhood improve the prognosis of the disease. FH is underdiagnosed resulting in premature death due to cardiovascular disease (CVD). To improve diagnosis, in 2015 the Argentine Society of Pediatrics proposed a universal screening program at school age. It is relevant, therefore, for the pediatrician to be able to diagnose hypercholesterolemia and differentiate monogenic or familial from secondary hypercholesterolemia (AU)


Subject(s)
Humans , Child, Preschool , Child , Adolescent , Cardiovascular Diseases/prevention & control , Cholesterol/metabolism , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/physiopathology , Hyperlipoproteinemia Type II/genetics , Hyperlipoproteinemia Type II/therapy , Mass Screening , Diagnosis, Differential , Anticholesteremic Agents/therapeutic use
13.
Arch. argent. pediatr ; 117(1): 41-47, feb. 2019. tab
Article in English, Spanish | LILACS, BINACIS | ID: biblio-983775

ABSTRACT

Introducción.La hipercolesterolemia en los padres sería mejor predictor de hipercolesterolemia en niños que la historia clínica familiar. Objetivos. Comparar las fuerzas de asociación y los valores de predicción de la hipercolesterolemia en padres y la historia clínica familiar positiva con la hipercolesterolemia en hijos. Material y métodos. Estudio analítico, transversal. Se dosó colesterolemia en niños ≥ 6 y < 12 años y sus padres biológicos. Se realizó una encuesta a los padres. Se evaluó la asociación mediante el cálculo de odds ratio. Se determinó su valor de predicción. Se estudió la relación entre la hipercolesterolemia en padres y en hijos usando la regresión multinivel. Resultados. Se evaluaron 332 niños, 304 madres y 206 padres. El análisis entre uno/ambos progenitores con colesterolemia ≥ 240 mg/dl y niños ≥ 200 mg/dl mostró OR= 6,40; IC95 % =2,85-14,48; p <0,0001; sensibilidad= 69 %; espedhcidad= 74 %; valor predictivo positivo (VPP)= 34 %; valor predictivo negativo (VPN)= 93 %; razones de verosimilitud positiva (RVP)= 2,69; negativa (RVN)= 0,42. La historia clínica familiar vs. niños con colesterolemia ≥ 200 arrojó OR= 1,86; IC95 %= 0,84-4,11; p= 0,1272; sensibilidad= 69 %; especificidad= 46 %; VPP= 19 %; VPN= 89 %; RVP= 1,27; RVN= 0,68. Los hijos tuvieron 2,9 y 2,5 más mg/dl de colesterol por cada 10 mg/dl de aumento en colesterol en madres y padres, respectivamente. Conclusiones: La hipercolesterolemia en padres se asoció significativamente con la hipercolesterolemia en hijos y mostró mayor poder de predicción que la historia clínica familiar positiva.


Introduction. Parental hypercholesterolemia would be a better predictor of hypercholesterolemia than family medical history in children. Objectives. To compare the strength of association and predictive values of parental hypercholesterolemia versus a positive family history in pediatric hypercholesterolemia. Material and methods. Cross-sectional, analytical study. Cholesterol levels were measured in children aged ≥ 6 and < 12 years and in their biological parents. A survey was administered to parents. The association was estimated using the odds ratio (OR), and its predictive value was determined. The relationship between hypercholesterolemia in parents and their children was studied with multilevel regression. Results. A total of 332 children, 304 mothers, and 206 fathers were assessed. A cholesterol level ≥ 240 mg/dL in one or both parents and ≥ 200 mg/dL in children showed: OR= 6.40; 95 % confidence interval (CI)= 2.85-14.48; p < 0.0001; sensitivity= 69 %; specihcity= 74 %; positive predictive value (PPV)= 34 %; negative predictive value (NPV)= 93 %; positive likelihood ratio (LR+)= 2.69; negative likelihood ratio (LR-)= 0.42. Family medical history versus children with cholesterol level ≥ 200 showed: OR= 1.86; 95 % CI= 0.84-4.11; p= 0.1272; sensitivity= 69 %; specihcity= 46 %; PPV= 19 %; NPV= 89 %; LR+= 1.27; LR-= 0.68. Cholesterol was 2.9 and 2.5 mg/dL higher per every 10 mg/dL of increased cholesterol in mothers and fathers, respectively. Conclusions: Parental hypercholesterolemia was significantly associated with hypercholesterolemia in children and showed a higher predictive power than a positive family medical history.


Subject(s)
Humans , Child , Adult , Middle Aged , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/blood , Medical History Taking , Research , Cross-Sectional Studies
14.
Rev. Soc. Cardiol. Estado de Säo Paulo ; 29(1 (Supl)): 67-71, jan.-mar. 2019. tab
Article in English, Portuguese | LILACS | ID: biblio-1015109

ABSTRACT

Comparar a prevalência dos fatores de risco para doenças cardiovasculares em pacientes com fenótipo de HF com e sem mutação. Métodos: Estudo transversal com pacientes que apresentam níveis de LDL-c ≥ 190 mg/dl e história pessoal ou familiar de hipercolesterolemia com diagnóstico genético positivo ou negativo. Foi aplicado um questionário padronizado para obtenção de informações sobre os fatores de risco cardiovascular (idade, sexo, perfil bioquímico, histórico de DCV, tabagismo, HAS, DM tipo II e estado nutricional). Também foram realizadas avaliações antropométricas e laboratoriais. Os dados foram analisados no software IBM® SPSS® Statistics versão 21 e o nível de significância estatística foi estabelecido em p < 0,05. Resultados: Foram avaliados 103 pacientes de ambos os sexos (67% mulheres) com média de idade de 55,27 ± 15,07 anos. Trinta e três pacientes tinham diagnóstico de HF. A comorbidade mais prevalente foi a hipertensão arterial sistêmica (65,05%), seguida de sobrepeso/obesidade (57,28%) e diabetes mellitus tipo II (26,21%). Conclusão: Portadores de HF apresentaram menor prevalência de FR cardiovasculares, quando comparados com pacientes sem a mutação. No entanto, eles ainda merecem atenção diferenciada e focada no manejo de FR modificáveis, uma vez que a presença de pelo menos um FR já aumenta significantemente o risco CV nessa população


To compare the prevalence of risk factors for cardiovascular disease in patients with FH phenotype with and without mutation. Methods: A cross-sectional study with patients who present LDL-c levels ≥190mg/dL and a personal or family history of hypercholesterolemia with positive or negative genetic diagnosis. We applied a standardized questionnaire to obtain information on cardiovascular risk factors (age, sex, biochemical profile, history of CVD, smoking, hypertension, type 2 diabetes mellitus and nutritional status). Anthropometric measurements and laboratory tests were also performed. The data were analyzed using version 21 of the IBM® SPSS® Statistics software and statistical significance was established as p <0.05. Results: We studied 103 patients of both sexes (67% female) with a mean age of 55.27 ± 15.07 years. Thirty-three patients had a diagnosis of FH. The most prevalent comorbidity was systemic hypertension (65.05%), followed by overweight/obesity (57.28%) and type 2 diabetes mellitus (26.21%). Conclusion: The population with FH had lower cardiovascular RF prevalence when compared with patients without the mutation. However, they still merit differentiated care focused on the management of modifiable RFs, since the presence of at least one RF already significantly increases the CV risk in this population


Subject(s)
Humans , Male , Female , Middle Aged , Phenotype , Cardiovascular Diseases , Prevalence , Risk Factors , Hyperlipoproteinemia Type II , Anthropometry , Statistical Analysis , Surveys and Questionnaires , Diabetes Mellitus , Atherosclerosis , Overweight , Observational Study , Hypertension , Obesity
15.
São Paulo; s.n; s.n; 2019. 140 p. tab, graf, ilus.
Thesis in Portuguese | LILACS | ID: biblio-1007576

ABSTRACT

A Hipercolesterolemia Familial (HF) é uma doença genética do metabolismo das lipoproteínas, caracterizada pelo aumento do colesterol plasmático, transportado principalmente pela lipoproteína de baixa densidade (LDL). A HF é causada principalmente por mutações nos genes LDLR, APOB e PCSK9. As mutações conhecidas na PCSK9 podem levar ao aumento ou diminuição da função proteolítica da proteína, as quais são associadas ao aumento ou diminuição da LDL-c plasmática, respectivamente. Com o projeto genoma humano surgiram novos métodos de sequenciamento, o que resultou em um grande número de novas variantes genéticas relacionadas à HF. Entretanto, os mecanismos pelos quais essas variantes influenciam na concentração do colesterol e sua interferência na resposta terapêutica não estão totalmente elucidados. O objetivo do presente trabalho foi avaliar in vitro o efeito de variantes na região codificadora e reguladora do gene PCSK9 identificadas em pacientes HF utilizando sequenciamento de nova geração. Para a caracterização funcional das variantes na região codificadora da PCSK9, primeiramente foi avaliado o impacto dessas variantes na interação PCSK9-LDLR via Docking molecular. Células HEK293FT foram transfectadas com as diferentes construções da PCSK9, e posteriormente, foram utilizadas em ensaios para avaliar a atividade do LDLR e a internalização de LDL por citometria de fluxo. Para as variantes na região reguladora da PCSK9, foi realizado uma predição in silico do possível efeito de variantes na região 3UTR na ligação de miRNAs. A avalição da interação entre os miRNAs preditos, e a região 3UTR da PCSK9, e o possível impacto nessa interação na presença de variantes na região 3UTR, foi realizada em células HEK293FT transfectadas com um plasmídeo contendo a 3UTR da PCSK9 e um gene repórter da Gaussia luciferase, juntamente com um plasmídeo de expressão contendo os miRNAs de interesse. Foi também estudado o efeito dos miRNAs preditos sobre a expressão, RNAm e proteína, da PCSK9 via RT-qPCR e Western blot, em células HepG2. Foram identificadas 9 variantes na região codificadora da PCSK9, e duas, E32K e R469W, foram selecionadas para os ensaios posteriores. Para a R469W foi observada uma possível alteração conformacional a qual poderia aumentar a afinidade da PCSK9 pelo LDLR. Para a E32K, uma possível associação com HF foi observada em uma família brasileira com ascendência japonesa. As variantes E32K e R469W apresentaram uma redução na atividade do LDLR de 5 e 11%, respectivamente em comparação a PCSK9-WT. Entretanto, não foram observadas reduções estaticamente significativas na atividade do LDLR e na internalização da LDL em células transfectadas com ambas as variantes. Dez variantes foram encontradas na região 3UTR da PCSK9, entre elas três foram selecionadas por impactar a ligação de quatro miRNAs. Nossos dados demonstraram uma redução significativa na expressão da PCSK9 em células HepG2 transfectadas com os miR-4721 e miR-564 (p=0,036 e p=0,010, respectivamente). Porém, não foi observada diferenças na expressão da luciferase em células transfectadas com esses miRNAs, não sendo possível validar a interação miRNA-RNAm. As variantes no gene PCSK9 identificadas no nosso estudo podem não explicar individualmente o fenótipo HF, mas podem contribuir para a severidade da doença juntamente com outras variantes em outros genes


Familial Hypercholesterolemia (FH) is a genetic disorder of lipoprotein metabolism, characterized by elevated plasma cholesterol levels, mostly carried by low-density lipoprotein (LDL). FH is mainly caused by mutations in three genes, LDLR, APOB, and PCSK9. Gain-of-function mutations in PCSK9 reduce LDL receptor levels, resulting in high levels of LDL cholesterol in the plasma. Loss-of-function mutations lead to higher levels of the LDL receptor, resulting in lower LDL cholesterol levels. The Human Genome Project led to a faster technological development related to sequencing methods, which allowed identifying many novel variants associated with FH. However, the mechanisms by which these variants influence cholesterol levels and their interference in therapeutic response are not fully understood. The aim of the present study was to perform an in vitro characterization of the effect of PCSK9 variants identified in FH patients using Next-Generation Sequencing. For the functional characterization of variants in the coding region of PCSK9, the impact of these variants on PCSK9-LDLR interaction was evaluated by molecular docking. HEK293FT cells were transiently transfected with different PCSK9 constructs, and the amount of cell surface LDLR and LDL internalization were determined by flow cytometry. For the variants in PCSK9 3UTR region, an in silico prediction of PCSK9 3UTR variants in miRNA seed regions and target sites was performed. To determine whether the predicted miRNAs directly interact with PCSK9 3UTR region, HEK293FT cells were co-transfected with a vector containing a PCSK9 3'UTR region and a Gaussia luciferase reporter gene, together with an expression plasmid containing the miRNAs of interest. The effect of the predicted miRNAs on the expression of PCSK9 was evaluated using RT-qPCR and Western blot in HepG2 cells transiently transfected with miRNA mimics. Nine missense variants were identified in PCSK9 gene. E32K e R469W were chosen for further analysis. For R469W, a possible conformational change was observed that could increase the affinity of PCSK9 for LDLR, when compared to the wild-type. For E32K, a possible association with FH in a Brazilian family with Japanese ancestry was observed. E32K and R469W had a 5% and 11% decreased level of cell surface LDLR, respectively, as compared with WT-PCSK9. However, no significant reduction in the number of cell surface LDLR and LDL internalization was observed in transfected cells for both variants. Ten variants were found in PCSK9 3'UTR region, of which three were selected for affecting the binding of four miRNAs. Our data demonstrated a significant downregulation of PCSK9 in cells transfected with miR-4721 and miR-564 miRNA mimics, compared to cells transfected with a scramble control (p=0,036 and p=0,010, respectively). However, no differences in luciferase expression were observed in cells transfected with these miRNAs, therefore, it was not possible to experimentally validate miRNA-mRNA interaction. PCSK9 variants found in our study may not fully explain FH phenotype but may contribute to the severity of the disease together with other variants in other genes


Subject(s)
In Vitro Techniques/instrumentation , Proprotein Convertase 9/analysis , Pharmacogenomic Variants/genetics , Hyperlipoproteinemia Type II/diagnosis
16.
São Paulo; s.n; s.n; 2019. 72 p. ilus, graf, tab.
Thesis in Portuguese | LILACS | ID: biblio-999825

ABSTRACT

A hipercolesterolemia familial (HF) é uma doença autossômica dominante considerada como uma das formas mais graves de hiperlipidemia, assim como, a principal causa de morbi-mortalidade por ser o principal fator desencadeante da aterosclerose. A alteração primária e mais freqüente da HF incide no gene do receptor da LDL (LDLr), sabe-se que mais de 1600 mutações são descritas na literatura e a principal consequência dessas alterações resultam no comprometimento da remoção da LDL, aumentando a concentração plasmática. Atualmente, o ultrasequenciamento genômico permite gerar muitos dados, que podem identificar novas mutações gênicas de forma eficiente, reprodutiva e rápida. No entanto, somente a validação da nova mutação por atividade funcional pode realmente estabelecer a associação com a doença. O presente estudo tem como objetivo realizar a análise da atividade do receptor da LDL, identificadas através do sequenciamento de alto rendimento, no gene LDLr realizado pelo nosso grupo de pesquisa e correlacionar com dados clínicos, in vitro, in silico e estrutural. Para cumprir esta meta, os linfócitos T dos portadores de HF foram isolados do sangue periférico, cultivados e submetidos a estímulo para a expressão de receptores da LDL, incubados com LDL marcada para avaliação de ligação e interiorização pelas células de cada paciente. Dos 30 pacientes selecionados para esse estudo, 63% apresentaram mutação no LDLR, sendo que quase todas as variantes (p.Gly373Asp, p.Asp601His, p.Ile488Thr, p.Gly549Asp, p.Gly592Glu e Gly681Asp) são localizadas no segundo domínio entre os éxons 7 ao 14. De acordo com o docking molecular a variante p.Gly592Glu (rs137929307), que já foi identificada na população polonesa, espanhola e brasileira, já relacionada com a HF, pode aumentar a interação do LDLr com a ApoB e consequentemente o modo de interação entre as proteínas, no estudo in vitro foi possível notar um aumento tanto na média de fluorescência da ligação e da ligação e interiorização em relação a quantidade de LDLr na superfície celular


Familial hypercholesterolemia (HF) is an autosomal dominant disease considered as one of the most severe forms of hyperlipidemia, as well as the main cause of morbidity and mortality because it is the main triggering factor for atherosclerosis. The primary and more frequent alteration of the HF affects the LDL receptor gene (LDLr), it is known that more than 1600 mutations are described in the literature and the main consequence of these alterations results in the compromise of the LDL removal, increasing the plasma concentration. Nowadays, genomic ultrasequencing allows the generation of many data, which can identify new gene mutations efficiently, reproductively and rapidly. However, only the validation of the new functional activity mutation can actually establish association with the disease. The aim of the present study was to analyze LDL receptor activity, identified by high-throughput sequencing, in the LDLr gene performed by our research group and to correlate with clinical, in vitro, in silico and structural data. To meet this goal, the T lymphocytes from the HF carriers were isolated from the peripheral blood, cultured and challenged for the expression of LDL receptors, incubated with labeled LDL for binding assessment and internalization by the cells of each patient. Of the 30 patients selected for this study, 63% had a mutation in LDLR, and almost all variants (p.Gly373Asp, p.Asp601His, p.Ile488Thr, p.Gly549Asp, p.Gly592Glu and Gly681Asp) are located in the second domain between exons 7 to 14. According to the molecular docking the variant p.Gly592Glu (rs137929307), which has already been identified in the Polish, Spanish and Brazilian population, already related to HF, can increase the interaction of LDLr with ApoB and consequently the mode of interaction between proteins, in the in vitro study it was possible to note an increase in both the mean fluorescence of binding and binding and internalization in relation to the amount of LDLr on the cell surface


Subject(s)
Humans , Male , Female , Adult , Receptors, LDL/analysis , Validation Study , Lipoproteins, LDL/analysis , Lymphocytes , Molecular Docking Simulation/statistics & numerical data , Hyperlipoproteinemia Type II/classification
17.
São Paulo; s.n; s.n; 2019. 193 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-987685

ABSTRACT

A frequência de Hipercolesterolemia Familial (HF) ainda é desconhecida no Brasil, principalmente pela ausência de estudos com caracterização genotípica associada à fenotípica. Os dados epidemiológicos existentes se baseiam apenas no fenótipos e carecem do diagnóstico molecular confirmatório. O objetivo do presente estudo foi identificar as principais causas genéticas da HF em pacientes diagnosticados fenotipicamente através de um painel exômico com 61 genes a fim de contribuir para um sistema de confirmação do diagnostico molecular em uma amostra da população brasileira. Para isso foram incluídos 141 pacientes, não aparentados, portadores de HF atendidos pelo setor de dislipidemias do Instituto Dante Pazzanese de Cardiologia, Laboratório de Analises Clinicas da Faculdade de Ciências Farmacêuticas da Universidade Federal do Rio Grande do Norte e do Programa Hipercol Brasil do Instituto do Coração. As amostras de sangue periférico foram obtidas para determinações fenotípicas laboratoriais e extração de DNA genômico. A biblioteca de DNA foi construída utilizando o kit Nextera® Rapid Capture Enrichment Custom enriquecendo os éxons de 61 genes que direta ou indiretamente estão relacionados com metabolismo do colesterol. O ultrassequenciamento foi realizado utilizando kit MiSeq Reagent (300 a 500 ciclos) na plataforma MiSeq (Illumina). Os resultados de sequenciamento foram inicialmente alinhados a uma sequência referência e analisados para eliminação de falsos positivos, segundo os parâmetros de qualidade, tais como: cobertura mínima de 30x, frequência do alelo alterado maior que 20% e diferença da distribuição das leituras entre as sequências nucleotídicas menor que 15%. Foram identificadas 472 diferentes variantes em 56 dos genes presentes no painel, sendo 45 consideradas como não descritas. Nos genes APOA1, APOA2, LIPC, RBP4 e TIMP1 não foram observadas variantes dentro dos critérios estabelecidos. Das variantes observadas 25 identificadas em 30 (21,2%) pacientes já tinha sido publicadas em relação à HF nos três principais genes (LDLR, APOB e PCSK9), confirmando o diagnóstico. Foi caracterizado genotipicamente outras dislipidemias primárias em 7 pacientes, sem diagnóstico molecular de HF, através de variantes identificadas no ultrassequenciamento em outros genes. Dos 104 pacientes que não possuíam nenhuma variante já previamente caracterizada, 69 possuíam variantes relacionados com o metabolismo do colesterol. As variantes sem patogenicidade conhecida foram avaliadas através de ferramentas de predição in silico e 22 delas possuíam características sugestivas de patogenicidade em pelo menos 4 das ferramentas utilizadas, duas delas também mostraram alterar a estrutura da proteína segundo análises de docking molecular. Foram identificadas também 223 variantes em região não transcritas (UTR). Quando realizada as análises estatística de todas as variantes identificadas, observamos associação de 13 variantes com concentrações mais elevadas de colesterol da LDL, 5 com concentrações mais elevadas de apolipoproteina B-100, 5 com concentrações mais elevadas de colesterol total, 6 com presença de arco córneo, 2 com manifestação de xantelasmas, 2 com ausência de xantomas e 3 com a presença de doença arterial coronariana. Dessas 6 variantes já haviam sido previamente descritas com HF ou algum outro fenótipo associado e 2 não tinham citação na literatura pesquisada, mas possuíam característica patogênica para a proteína segundo as ferramentas de predição in silico. Este estudo permitiu a identificação das causas genéticas da HF em pacientes brasileiros diagnosticados fenotipicamente, mostrando que a técnica escolhida permitiu caracterizar 21,2% dos pacientes. Além disso, foi possível identificar outras dislipidemias primárias e caracterizar algumas variantes que, apesar de necessitarem serem validadas, indicam uma possível associação com a HF, aumentando o esclarecimento do fenótipo com o genótipo para 74,5%. Este estudo também possibilitou a identificação de novas variantes que devem ser avaliadas para confirmar associação com a doença e utilizar para o diagnóstico propondo um novo painel poligênico


The frequency of Familial Hypercholesterolemia (FH) is still unknown in Brazil, mainly due to the absence of studies with genotypic characterization associated with phenotype. Existing epidemiological data are based only on the phenotypes and lack the confirmatory molecular diagnosis. The aim of the present study was to identify main genetic causes of FH in patients diagnosed phenotypically through an exomic panel with 61 genes in order to contribute to a system of confirmation molecular diagnosis in a sample of the Brazilian population. To this end, 141 non-related patients with FH treated by the dyslipidemia sector of the Institute Dante Pazzanese of Cardiology, Clinical Analysis Laboratory of the Faculty of Pharmaceutical Sciences of the University Federal of Rio Grande do Norte and the Hipercol Brazil Program of the Heart Institute. Peripheral blood samples were obtained for laboratory phenotypic determinations and extraction of genomic DNA. The DNA library was constructed using the Nextera® Rapid Capture Enrichment Custom kit, enriching with éxons of 61 genes that are directly or indirectly related to cholesterol metabolism. Ultrasequencing was performed using MiSeq Reagent kit (300 to 500 cycles) on the MiSeq platform (Illumina). The sequencing results were initially aligned to a reference sequence and analyzed for false positive elimination according to quality parameters such as: minimum coverage of 30x, altered allele frequency greater than 20%, and difference in the distribution of reads between sequences nucleotides less than 15%. 472 different variants were identified in 56 of the genes present in the panel, of which 45 were considered not described. In the APOA1, APOA2, LIPC, RBP4 and TIMP1 genes no variants were observed within the established criteria. In 25 of the variants observed presents in 30 (21.2%) patients had already been published in relation to FH in the three main genes (LDLR, APOB and PCSK9), confirming the diagnosis. Other primary dyslipidemias were caracterized genotypically in 7 patients, without molecular diagnosis of HF, through variants identified in ultrasequencing in other genes. Of the 104 patients who did not have any previously characterized variant, 69 had variants related to cholesterol metabolism. The variants without known pathogenicity were evaluated using in silico prediction tools and 22 of them had characteristics suggestive of pathogenicity at least 4 of the tools used, two of them also showed to alter the structure of the protein according to molecular docking analyzes. Were also identified 223 non-transcribed region (UTR) variants. Statistical analysis of all the variants identified showed association of 13 variants with higher concentrations of LDL cholesterol, 5 with higher concentrations of apolipoprotein B-100, 5 with higher concentrations of total cholesterol, 6 with presence of an arc corneal, 2 with manifestation of xanthelasms, 2 with absence of xanthomas and 3 with the presence of coronary artery disease. Of these 6 variants had previously been described with HF or some other associated phenotype and 2 had no citation in the researched literature, but had a pathogenic characteristic for the protein according to in silico prediction tools. This study allowed the identification of the genetic causes of FH in Brazilian patients diagnosed phenotypically, showing that the technique chosen allowed to characterize 21.2% of the patients. In addition, it was possible to identify other primary dyslipidemias and to characterize some variants that, although they need to be validated, indicate a possible association with HF, increasing the clarification of the phenotype with the genotype to 74.5%. This study also allowed the identification of new variants that should be evaluated to confirm association with the disease and to use for the diagnosis proposing a new polygenic panel


Subject(s)
Humans , Male , Female , Genes/genetics , Hyperlipoproteinemia Type II/genetics , Apolipoproteins B/analysis , Gene Library , Proprotein Convertase 9/analysis
19.
Article in Korean | WPRIM | ID: wpr-766824

ABSTRACT

BACKGROUND: The patients with familial hypercholesterolemia (FH) suffer from early onset atherosclerotic vascular disease due to high level of cholesterol and subsequent vascular inflammation, especially in the form of coronary artery disease. We investigated the clinical characteristics of FH associated cerebral infarction and its possible mechanism. METHODS: Between January 2014 and May 2017, acute cerebral infarction patients who admitted to Chung-Ang University Hospital were reviewed from stroke registry and the diagnosis of FH was made based on the Dutch Lipid Clinic Network Diagnostic Criteria for FH. We reviewed their initial laboratory and brain imaging information, prescribed medication and followed lipid profile after discharge. Stroke mechanism was determined based on Trial of ORG 10172 in Acute Stroke Treatment classification. RESULTS: Among 1,401 acute cerebral infarction or transient ischemic attack patients, one probable and three possible FH stroke patients were detected. All the patients denied of previous coronary artery disease history and initial lipid panel revealed high levels of total cholesterol (378±75 mg/dL) and low-density lipoprotein-cholesterol (238±56 mg/dL). Stroke mechanisms were heterogeneous, including one atherosclerotic, two vertebral artery dissection cases and one coagulation disorder. All the patients were combined with noticeable degree of intracranial atherosclerosis and were maintained with statin treatment. CONCLUSIONS: This study illustrates diverse stroke mechanism among stroke patients with FH. Further research is required to disclose exact incidence of FH among stroke population and effective treatment strategy.


Subject(s)
Atherosclerosis , Cerebral Infarction , Cholesterol , Classification , Coronary Artery Disease , Diagnosis , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hyperlipoproteinemia Type II , Incidence , Inflammation , Intracranial Arteriosclerosis , Ischemic Attack, Transient , Neuroimaging , Stroke , Vascular Diseases , Vertebral Artery Dissection
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