Identificación de variantes genéticas asociadas a hipercolesterolemia familiar en niños y adolescentes de la Región del Biobío, Chile / Identification of genetic variants associated with familial hypercholesterolemia in Chilean children and adolescents

Background: Familial hypercholesterolemia (FH) is commonly associated with mutations in-LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Aim: To identify genetic variants associated with FH in a population of children and adolescents with hypercholesterolemia or a family history of-demonstrated early CVD. Material and Methods: Clinical and biochemical parameters were evaluated, and nine genes related to FH were sequenced namely LDLR, APOB, PCSK9, LDLRAP1, LIPA, APOE, ABCG5, ABCG8 and STAP1, in 55 children and adolescents aged 1 to 18 years old, from non-consanguineous families. Results: Mutations associated with FH were found in 17 children and adolescents, corresponding to p.Asp47Asn, duplication of exons 13-15 and p.Ser326Cys of the LDLR gene; p.Glu204* and Ile268Met of the APOE gene. Thirteen patients were heterozygous, two homozygous, two compound heterozygous, and one double heterozygous. Conclusions: Children and adolescents carrying mutations associated with FH were found by selective screening, which constitutes the first stage in the identification of genetic variants in our country.

Percepção Inadequada do Risco Cardiovascular e Baixo Conhecimento sobre Hipercolesterolemia Familiar em Indivíduos com Hipercolesterolemia Grave / Cardiovascular Risk Misperception and Low Awareness of Familial Hypercholesterolemia in Individuals with Severe Hypercholesterolemia

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)

Portador Heterozigoto Composto de Hipercolesterolemia Familiar Causada por Variantes no LDLR / Compound Heterozygous Familial Hypercholesterolemia Caused by LDLR Variants

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.

The use of high-resolution MRI to detect thrombosis and lipid-rich carotid artery plaques in a patient with homozygous familial hypercholesterolemia

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.

Inhibidores de la PCSK9: una nueva era en el control del riesgo cardiovascular / PCSK9 inhibitors: a new era in the control of cardiovascular risk / Inibidores da PCSK9: uma nova era no controle do risco cardiovascular

Resumen: Las estatinas constituyen aún la pieza fundamental para el manejo del riesgo cardiovascular. Utilizadas en dosis de alta intensidad logran reducciones de colesterol asociado a lipoproteínas de baja densidad (C-LDL) de 50%-60%. Sin embargo, en pacientes con hipercolesterolemia severa, las estatinas solas o asociadas a ezetimibe pueden no ser suficientes para alcanzar los objetivos de descenso de C-LDL. Tal es el caso de las dislipemias genéticas como la hipercolesterolemia familiar. Lo mismo ocurre en pacientes con intolerancia total o parcial a estatinas, en los que se requiere de alternativas farmacológicas modernas que permitan reducir el riesgo cardiovascular elevado. En este escenario, los inhibidores de la proproteína convertasa subtilisina kexina tipo 9, se han convertido en una piedra angular para lograr no solo una reducción jamás antes vista del C-LDL, sino también del riesgo cardiovascular. La nueva evidencia posiciona a estos fármacos en un lugar de privilegio, siendo eficaces y bien tolerados, con el costo como principal limitante, a pesar de su marcado descenso en los últimos años.

Summary: Statins are still the fundamental piece for cardiovascular risk management. Used in doses of high intensity achieve reductions in cholesterol associated with low density lipoproteins of 50%-60%. However, in patients with severe hypercholesterolemia, statins alone or associated with ezetimibe may not be sufficient to achieve cholesterol associated with low density lipoproteins decrease targets. Such is the case of genetic dyslipidemias as familial hypercholesterolemia. Also in patients with total or partial statin intolerance, a modern pharmacological alternative is required to reduce high cardiovascular risk. In this scenario, proprotein convertase subtilisin kexin type 9 inhibitors have become a cornerstone to achieve not only a reduction never seen before of cholesterol associated with low density lipoproteins levels, but also of cardiovascular risk. These drugs are in a privilege position due to the new evidence, being effective and well tolerated, with cost as its main limitation despite its marked decline in recent years.

Resumo: As estatinas ainda são a peça fundamental da gestão de risco cardiovascular. Utilizada em dose de alta intensidade atinge reduções associadas com colesterol da lipoproteína de baixa densidade de 50%-60%. No entanto em pacientes com hipercolesterolemia grave, estatinas, sozinhas ou associadas a ezetimiba podem não ser suficientes para alcançar os objetivos de redução de colesterol da lipoproteína de baixa densidade. Tal é o caso das dislipidemias genéticas como a hipercolesterolemia familiar. O mesmo ocorre em pacientes com intolerância total ou parcial de estatinas, que exige modernas alternativas farmacológicas que permitem reduzir o risco cardiovascular alto. Neste panorama, os inibidores da pró-proteína convertasa subtilisina kexina tipo 9, se tornaram uma pedra angular para alcançar não apenas uma redução em nunca antes visto colesterol da lipoproteína de baixa densidade, mas de risco cardiovascular. Novas provas colocam essas drogas em um lugar de privilégio, por ser eficaz e bem tolerado, com o custo como sua principal limitante a pesar do seu grande declínio nos últimos anos.

Clinical, Anthropometric and Biochemical Characteristics of Patients with or without Genetically Confirmed Familial Hypercholesterolemia / Características Clínicas, Antropométricas e Bioquímicas de Pacientes com ou sem Diagnóstico Confirmado de Hipercolesterolemia Familiar

Abstract Background: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder, characterized by a high level of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular disease. Objective: To evaluate clinical and anthropometric characteristics of patients with the familiar hypercholesterolemia (FH) phenotype, with or without genetic confirmation of FH. Methods: Forty-five patients with LDL-C > 190 mg/dl were genotyped for six FH-related genes: LDLR, APOB, PCSK9, LDLRAP1, LIPA and APOE. Patients who tested positive for any of these mutations were considered to have genetically confirmed FH. The FH phenotype was classified according to the Dutch Lipid Clinic Network criteria. Results: Comparing patients with genetically confirmed FH to those without it, the former had a higher clinical score for FH, more often had xanthelasma and had higher LDL-C and apo B levels. There were significant correlations between LDL-C and the clinical point score for FH (R = 0.382, p = 0.037) and between LDL-C and body fat (R = 0.461, p = 0.01). However, patients with mutations did not have any correlation between LDL-C and other variables, while for those without a mutation, there was a correlation between LDL-C and the clinical point score. Conclusions: LDL-C correlated with the clinical point score and with body fat, both in the overall patient population and in patients without the genetic confirmation of FH. In those with genetically confirmed FH, there were no correlations between LDL-C and other clinical or biochemical variables in patients.

Resumo Fundamentos: A hipercolesterolemia familiar (HF) é uma doença autossômica dominante, caracterizada por altos níveis plasmáticos do colesterol da lipoproteína de baixa densidade (LDL-C) e pelo alto risco de desenvolvimento prematuro de doenças cardiovasculares. Objetivo: Avaliar características clínicas e antropométricas de pacientes com fenótipo para hipercolesterolemia familiar (HF), com ou sem diagnóstico genético de HF. Métodos: Quarenta e cinco pacientes com LDL-C > 190 mg/dL foram genotipados para seis genes relacionados com a HF: LDLR, APOB, PCSK9, LDLRAP1, LIPA e APOE. Pacientes que apresentaram resultado positivo para qualquer uma das mutações foram diagnosticados com HF por confirmação genética. O fenótipo para HF foi classificado pelo critério da Dutch Lipid Clinic Network. Resultados: Comparando os pacientes com a HF geneticamente confirmada com aqueles sem a confirmação, os primeiros apresentaram maior pontuação do escore para HF, uma maior frequência de xantelasma e maiores níveis de LDL-C e apo B. Houve correlações significativas entre o LDL-C e a pontuação do escore para HF (R = 0,382, p = 0,037) e entre LDL-C e gordura corporal (R = 0,461, p = 0,01). Os pacientes com mutações, no entanto, não apresentaram qualquer correlação entre o LDL-C e outras variáveis, enquanto aqueles sem mutação apresentaram correlação entre o LDL-C e a pontuação do escore. Conclusão: O LDL-C correlacionou-se com a pontuação do escore e com a gordura corporal, tanto na população total de pacientes quanto nos pacientes sem a confirmação genética de HF. Naqueles com HF geneticamente confirmada, não houve correlação entre o LDL-C e outras variáveis clínicas ou bioquímicas dos pacientes.

Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts / 전남의대학술지

We aimed to evaluate the prevalence of familial hypercholesterolaemia (FH) in a subject with hypercholesterolaemia from two population-based cohorts in South Korea. A total of 283 subjects with total cholesterol levels of 290 mg/dL (7.5 mmol/L) or higher were selected from the Namwon and Dong-gu Studies. We used next generation sequencing (NGS) to detect mutations in low-density lipoprotein receptors (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. We have confirmed 17 different mutations of the LDLR, APOB and PCSK9 in 23 subjects (8.1%). Eleven LDLR variants and one APOB variant have been previously reported. One LDLR and two PCSK9 rare variants were identified in the variants database, but not in the FH mutation database. Two novel LDLR variants were found, p.Leu680Val, and p.Thr734Phe. No LDLR, APOB or PCSK9 deletions nor insertions were found. When the subjects were restricted to 110 subjects with a total cholesterol ≥310 mg/dL, only 10 variants were found in the 10 subjects (9.1%). These results suggest that given the low prevalence of FH mutations in subjects with high total cholesterol levels, NGS-based testing for a population-based approach to FH detection may not be cost-effective.

Update on Familial Hypercholesterolemia: Diagnosis, Cardiovascular Risk, and Novel Therapeutics

In recent studies, the reported prevalence of heterozygous familial hypercholesterolemia (FH) has been higher than in previous reports. Although cascade genetic screening is a good option for efficient identification of affected patients, diagnosis using only clinical criteria is more common in real clinical practice. Cardiovascular risk is much higher in FH patients due to longstanding low density lipoprotein cholesterol (LDL-C) burden and is also influenced by other risk factors. Although guidelines emphasize aggressive LDL-C reduction, the majority of patients cannot reach the LDL-C goal by conventional pharmacotherapy. Novel therapeutics such as proprotein convertase subtilisin/kexin type 9 inhibitors have shown strong lipid lowering efficacy and are expected to improve treatment results in FH patients.

Interaction between Glucose and Lipid Metabolism: More than Diabetic Dyslipidemia

Glucose and lipid metabolism are linked to each other in many ways. The most important clinical manifestation of this interaction is diabetic dyslipidemia, characterized by elevated triglycerides, low high density lipoprotein cholesterol (HDL-C), and predominance of small-dense LDL particles. However, in the last decade we have learned that the interaction is much more complex. Hypertriglyceridemia and low HDL-C cannot only be the consequence but also the cause of a disturbed glucose metabolism. Furthermore, it is now well established that statins are associated with a small but significant increase in the risk for new onset diabetes. The underlying mechanisms are not completely understood but modulation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA)-reductase may play a central role as genetic data indicate that mutations resulting in lower HMG CoA-reductase activity are also associated with obesity, higher glucose concentrations and diabetes. Very interestingly, this statin induced increased risk for new onset type 2 diabetes is not detectable in subjects with familial hypercholesterolemia. Furthermore, patients with familial hypercholesterolemia seem to have a lower risk for type 2 diabetes, a phenomenon which seems to be dose-dependent (the higher the low density lipoprotein cholesterol, the lower the risk). Whether there is also an interaction between lipoprotein(a) and diabetes is still a matter of debate.