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Familial dysbetalipoproteinemia (FD) is a highly atherogenic genetically based lipid disorder with an underestimated actual prevalence. In recent years, several biochemical algorithms have been developed to diagnose FD using available laboratory tests. The practical applicability of FD diagnostic criteria and the prevalence of FD in Russia have not been previously assessed. We demonstrated that the diagnostic algorithms of FD, including the diagnostic apoB levels, require correction, taking into account the distribution of apoB levels in the population. At the same time, a triglycerides cutoff ≥ 1.5 mmol/L may be a useful tool in identifying subjects with FD. In this study, a high prevalence of FD was detected: 0.67% (one in 150) based on the ε2ε2 haplotype and triglycerides levels ≥ 1.5 mmol/L. We also analyzed the presence and pathogenicity of APOE variants associated with autosomal dominant FD in a large research sample.

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BACKGROUND: Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (IDL) in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown. OBJECTIVE: To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition. METHODS: Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE. RESULTS: PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%confidence interval (CI) 41-59 and very low-density lipoprotein (VLDL)-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than triglyceride (TG) in VLDL, IDL and low-density lipoprotein (LDL) (e.g. VLDL-C 48%, 95%CI 29-63%; and VLDL-TG 20%, 95%CI 6.3-41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons. CONCLUSION: PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated.

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The increased risk of cardiovascular disease in patients with dysbetalipoproteinemia (DBL) is well documented and is associated with the dysfunctional metabolism of remnant lipoproteins. Although these patients are known to respond well to lipid-lowering medication including statins and fibrates, the best dietary approach to lower remnant lipoprotein accumulation and to prevent cardiovascular outcomes remain unclear. Indeed, current evidence is based on studies published mainly in the 1970s, which comprise small sample sizes and methodological limitations. This review aims to summarize nutritional studies performed in DBL patients to date and to discuss potential avenues in this field and future areas of research.

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BACKGROUND: apo (apolipoprotein) E has crucial role in lipid metabolism. The genetic variation in APOE gene is associated with monogenic disorders and contributes to polygenic hypercholesterolemia and to interindividual variability in cholesterol. APOE rare variants may be involved in the phenotype of genetic hyperlipidemias. METHODS: Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a Lipid Unit (n=3667) and 822 random subjects from the Aragon Workers Health Study. Binding affinity of VLDL (very low-density lipoprotein) to LDL receptor of pathogenic predicted apoE variants was analyzed in vitro. Lipoprotein particle number, size, and composition were studied by nuclear magnetic resonance. RESULTS: In addition to common polymorphisms giving rise to APOE2 and APOE4, 14 gene variants were found in exon 4 of APOE in 65 subjects. p.(Leu167del) in 8 patients with isolated hypercholesterolemia and in 8 patients with combined hyperlipidemia. Subjects with p.(Arg121Trp), p.(Gly145Asp), p.(Arg154Ser), p.(Arg163Cys), p.(Arg165Trp), and p.(Arg168His) variants met dysbetalipoproteinemia lipid criteria and were confirmed by nuclear magnetic resonance. VLDL affinity for the LDL receptor of p.(Arg163Cys) and p.(Arg165Trp) heterozygous carriers had intermedium affinity between APOE2/2 and APOE3/3. p.(Gly145Asp) and p.(Pro220Leu) variants had higher affinity than APOE3/3. CONCLUSIONS: APOE genetic variation contributes to the development of combined hyperlipidemia, usually dysbetalipoproteinemia, and familial hypercholesterolemia. The lipid phenotype in heterozygous for dysbetalipoproteinemia-associated mutations is milder than the homozygous APOE2/2-associated phenotype. Subjects with dysbetalipoproteinemia and absence of APOE2/2 are good candidates for the study of pathogenic variants in APOE. However, more investigation is required to elucidate the significance of rarer variants of apoE.

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BACKGROUND: Familial dysbetalipoproteinemia (FDBL) is a monogenic disease due to variants in APOE with a highly variable phenotype. Current diagnostic lipid-based methods have important limitations. The objective is twofold: to define characteristics of dysbetalipoproteinemia (DBL) based on the analysis of APOE in patients from a lipid unit and in a sample from the general population, and to propose a screening algorithm for FDBL. METHODS: Lipids and APOE genotype from consecutive unrelated subjects from Miguel Servet University Hospital (MSUH) (n 3603), subjects from the general population participants of the Aragon Workers Health Study (AWHS) (n 4981), and selected subjects from external lipid units (Ext) (n 390) were used to define DBL criteria and to train and validate a screening tool. RESULTS: Thirty-five subjects from MSUH, 21 subjects from AWHS, and 31 subjects from Ext were APOE2/2 homozygous. The combination of non high-density lipoprotein cholesterol (non-HDLc)/apoB 1.7 plus triglycerides/apoB 1.35, in mg/dL (non-HDLc [mmol/L]/apolipoprotein B (apoB) [g/L] 4.4 and triglycerides [mmol/L]/apoB [g/L] 3.5), provided the best diagnostic performance for the identification of subjects with hyperlipidemia and APOE2/2 genotype (sensitivity 100 in the 3 cohorts, and specificity 92.8 [MSUH], 80.9 [AWHS], and 77.6 [Ext]). This improves the performance of previous algorithms. Similar sensitivity and specificity were observed in APOE2/2 subjects receiving lipid-lowering drugs. CONCLUSIONS: The combination of non-HDLc/apoB and triglycerides/apoB ratios is a valuable tool to diagnose DBL in patients with hyperlipidemia with or without lipid-lowering drugs. FDBL diagnosis requires DBL and the presence of a compatible APOE genotype. Most adult APOE2/2 subjects express DBL, making FDBL as common as familial hypercholesterolemia in the population.

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BACKGROUND: Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options. OBJECTIVES: To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD. METHODS: A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins. RESULTS: In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load. CONCLUSIONS: Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.

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AIM: To compare LDL-C concentrations using the Friedewald formula, the Martin-Hopkins formula, a direct assay and polyacrylamide gradient gel electrophoresis (PGGE) to the reference standard density gradient ultracentrifugation in patients with Familial Dysbetalipoproteinemia (FD) patients. We also compared non-HDL-cholesterol concentrations by two methods. METHODS: For this study data from 28 patients with genetically confirmed FD from the placebo arm of the EVOLVE-FD trial were used. Four different methods for determining LDL-C were compared with ultracentrifugation. Non-HDL-C was measured with standard assays and compared to ultracentrifugation. Correlation coefficients and Bland-Altman plots were used to compare the methods. RESULTS: Mean age of the 28 FD patients was 62 ± 9 years, 43 % were female and 93 % had an ɛ2ɛ2 genotype. LDL-C determined by Friedewald (R2 = 0.62, p <0.01), Martin-Hopkins (R2 = 0.50, p = 0.01) and the direct assay (R2 = 0.41, p = 0.03) correlated with density gradient ultracentrifugation. However, Bland-Altman plots showed considerable over- or underestimation by the four methods compared to ultracentrifugation. Non-HDL-C showed good correlation and agreement. CONCLUSION: In patients with FD, all four methods investigated over- or underestimated LDL-C concentrations compared with ultracentrifugation. In contrast, standard non-HDL-C assays performed well, emphasizing the use of non-HDL-C in patients with FD.

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INTRODUCCIÓN: La apolipoproteína ApoE es una proteína reguladora del transporte de colesterol y del metabolismo a nivel periférico y del sistema nervioso central (SNC). Debido a su efecto pleitrópico, sus diferentes variaciones pueden generar un gran impacto en el diagnóstico y pronóstico de multitud de enfermedades prevalentes; entre las que se incluyen diferentes condiciones de tipo cardiovascular o neurodegenerativas. Concretamente, el alelo ε4 está relacionado con mayor riesgo de desórdenes cerebrovasculares y el desarrollo de enfermedad de Alzheimer (EA) de inicio tardío; mientras que el alelo ε2 es considerado el de riesgo para el desarrollo de las dislipemias como la disbetalipoproteinemia familiar (DBLP). La determinación del genotipo de apoE por la tecnología de reacción en cadena de la polimerasa a tiempo real (qPCR) se presenta como una alternativa a otros métodos de genotipado ampliamente usados y que cuentan con una serie de limitaciones para su implementación en la práctica clínica.OBJETIVO: Los objetivos de este informe fueron la evaluación de la determinación de apoE por qPCR en el diagnóstico de la DBLP; y su integración como factor predictor, dentro de un modelo pronóstico con el objetivo de establecer el riesgo de EA de inicio tardío. Este informe pretende evaluar la capacidad del uso de esta tecnología en el contexto descrito, y su comparativa respecto a otras técnicas genéticas (y/o fenotípicas, en el caso de DBLP). METODOLOGÍA: Revisión sistemática de la evidencia científica que evalúa el uso de qPCR para el genotipado de apoE en el contexo del objetivo del estudio. Se consultaron las siguientes bases de datos: Medline, Embase, The Cochrane Library, Web of Science, International HTA Database. Además, se realizó una búsqueda de ensayos clínicos en curso: ClinicalTrial.gov, Current Controlled Trial (ISRCTN registry), International Clinical Trials Registry Platform (WHO) y EU Clinical Trials Register. RESULTADOS: DBLP: Se recuperaron un total de 284 referencias bibliográficas, de las cuales, únicamente un estudio cumplió con los criterios de inclusión1. La mayoría de los trabajos fueron descartados por emplear otro tipo de técnicas para el genotipado de apoE, principalmente la reacción en cadena de la polimerasa con análisis del polimorfismo de los fragmentos de restricción (PCR-RLFP) o por secuenciación. En el único estudio incluido donde emplean esta técnica, su objetivo se centra en la puesta a punto de un algoritmo diagnóstico para el cribado de la DBLP1. Los autores incluyen una nueva definición de hiperlipidemia, junto con la descripción de unos valores umbrales a partir del perfil lipídico del paciente. Además de poner a punto el criterio diagnóstico, éste también es evaluado respecto a otros algoritmos disponibles en la literatura; obteniéndose unos valores de sensibilidad, exactitud diagnóstica y/o especificidades más altos que con los otros criterios comparados2-5. Sin embargo, este estudio cuenta con algunas limitaciones como es la heterogeneidad de la población de estudio o la ausencia de grupos comparadores de la tecnología de caracterización de apoE respecto a otras técnicas1. EA de inicio tardío: Se identificaron un total de 818 estudios de los cuales ninguno de ellos cumplió con la premisa del uso de la qPCR para apoE integrado en un modelo predictivo pronóstico de EA de inicio tardío. La mayoría de las publicaciones que se identificaron hacían uso de la qPCR para el genotipado de apoE para su inclusión en modelos de tipo diagnóstico. Atendiendo a uno de los objetivos del informe, en el proceso de búsqueda bibliográfica se recopilaron un total de 8 estudios que recogían modelos de tipo pronóstico en los que se empleaban otras técnicas genéticas diferentes a la qPCR6-12. En la mayoría de los estudios los pacientes procedían de bases de datos donde la técnica empleada para el análisis de apoE era la PCR-RFLP7,9,11-13. Entre los factores predictores más representados junto con apoE, son la edad, sexo, función cognitiva o diversos parámetros de imagen como el análisis de regresión tipo Cox de las regiones de interés (COX-ROI), análisis de covarianza de regiones de interés (ANCOVA-ROI) o imagen por ressonância magnética (IRM) y biomarcadores en sangre como beta amiloide Aß1-42 ó la proteína tau fosforilada (p-tau). DISCUSIÓN: En referencia a la evaluación de esta tecnología como método de determinación del genotipado de apoE en el diagnóstico de la DBLP, su uso reside en una prueba de tipo de confirmatorio que normalente acompaña a otras determinaciones del perfil lipídico. Además de la ausencia de trabajos en los que sea la qPCR el procedimiento de elección, en el único estudio identificado no se contempla un ensayo comparativo con otras técnicas genéticas o fenotípicas para la caracterización de apoE. Por otro lado, hay que tener en consideración que un 10% de las DBLP se presentan con un patrón de herencia de tipo autosómico dominante; y por tanto diferente al típico patrón de alelos Ɛ2/Ɛ2, por lo que el empleo de la técnica de qPCR podría contribuir a infradiagnosticar esta condición. En referencia al empleo del genotipado de apoE por qPCR integrado en un modelo predictivo pronóstico de EA de inicio tardío no se encontraron estudios que apoyen su uso. Los modelos identificados con este propósito y que además incluyen el genotipado de apoE, aún sin ser la qPCR la técnica de elección, se tratan de modelos que ofrecen insuficiente información para ser usados en la práctica clínica habitual y que permitan establecer el riesgo a nivel individual de desarrollar EA de inicio tardío. Por otro lado, conviene tener en cuenta que tanto la DBLP como la EA se trata de patologías de carácter multifactorial donde, es necesario la confluencia de varios factores, más allá de ser portador de un determinado patrón genético, para que se desarrolle la enfermedad. En el caso de la DBLP, contar con este tipo de información podría considerarse una ventaja, debido fundamentalmente a la existencia de un tratamiento farmacológico eficaz y/u otras medidas preventivas potencialmente instaurables. Por el contrario, en relación a la EA de inicio tardío, conviene tener en cuenta las consideraciones éticas y legales que acarrean la disponibilidad de esta información ligada únicamente al concepto de "genes de susceptibilidad" o "riesgo aumentado"; debido al gran impacto a nivel social, emocional y económico tanto para el paciente como para su entorno, además de no contar con una aproximación terapéutica que ofrecer al paciente para impedir su desarrollo. CONCLUSIONES: El gen apoE tiene un papel biológico relevante en el metabolismo humano de los lípidos, lo que ha llevado al desarrollo de distintas técnicas que permiten analizar los polimorfismos del mismo y las isoformas que se generan. No hay suficiente evidencia científica que apoye la inclusión de la técnica de qPCR como método de genotipado de apoE en la práctica clínica diaria ni que implique un valor añadido dentro de un algoritmo diagnóstico de la DBLP, ni como determinación a integrar en un modelo pronóstico de detección temprana de EA de inicio tardío, respecto a otras técnicas de genotipado disponibles actualmente. En un entorno de medicina de precisión e independientemente de la técnica de genotipado empleada para la caracterización del gen apoE, disponer de esta información puede ser relevante para, de una manera individualizada, en personas con manifestaciones y/o alteraciones bioquímicas lipídicas, la adopción temprana de medidas terapéuticas en el caso de la DBLP homocigotas y; en personas con sospecha de EA de inicio tardío (60 años o más de edad), la puesta en marcha de medidas que permitan modificar los factores de riesgo que puedan estar bajo el control de la persona y familiares, teniendo presentes los recursos disponibles en su entorno para informar adecuadamente a la persona y acceder a los mismos en caso de necesidad.

INTRODUCTION: Apolipoprotein ApoE is a protein that regulates cholesterol transport and metabolism in the peripheral and central nervous systems. Due to its pleiotropic effect, its different variations can have a major impact on the diagnosis and prognosis of a variety of prevalent diseases, including several cardiovascular and neurodegenerative conditions. Specifically, the ε4 allele is associated with an increased risk of cerebrovascular disorders and the development of late-onset Alzheimer's disease, whereas the ε2 allele is considered the risk one for the development of dyslipidaemias such as familial dysbetalipoproteinemia. ApoE genotyping by real-time polymerase chain reaction (qPCR) technology is presented as an alternative to other widely used genotyping methods, which have a large number of limitations for the implementation in clinical practice. OBJECTIVE: The objectives of this report were to evaluate apoE determination by qPCR in the diagnosis of familial dysbetalipoproteinemia; and its integration as a predictive factor within a prognostic model with the aim of establishing the risk of late-onset Alzheimer's disease. This report aims to evaluate the use of this technology in the described context, and its comparison with other genetic (and/or phenotypic, in the case of familial dysbetalipoproteinemia) techniques. Methodology: Systematic review of the scientific evidence evaluating the use of qPCR for apoE genotyping in the described context. The following databases were consulted: Medline, Embase, The Cochrane Library, Web of Science, International HTA Database and TESEO. In addition, a search for ongoing clinical trials were also conducted: ClinicalTrial.gov, Current Controlled Trial (ISRCTN registry), International Clinical Trials Registry Platform (WHO) and EU Clinical Trials Register. RESULTS: Familial dysbetalipoproteinemia: A total of 284 bibliographic references were identified of which only one study met the inclusion criteria1. Most of the studies were excluded because they used other techniques for apoE genotyping, mainly polymerase chain reaction with restriction fragment polymorphism analysis (PCR-RLFP) or sequencing. The only included study that used this apoE genotyping techniques is focused on developing a diagnostic algorithm for familial dysbetalipoproteinemia screening1. The authors introduce a new definition of hyperlipidaemia, and a description of threshold values based on patient's lipid profile. In addition to develop a diagnostic criterion, it is also evaluated against other algorithms available in the literature, yielding higher values for sensitivity, diagnostic accuracy and/or specificity than other criteria compared2-5. However, this study has some limitations such as the heterogeneity of the population or the absence of comparator groups of the apoE characterisation technology with respect to other techniques. Alzheimer's disease: A total of 818 studies were identified, none of which fulfilled the premise of using qPCR for apoE integrated into a predictive prognostic model for lateonset Alzheimer's disease. Most of the publications identified used qPCR for apoE genotyping for inclusion in diagnostic models. According to one of the objectives of the report, a total of 8 studies were collected in the literature search process that included prognostic models using genetic technique other than qPCR6-12. In the majority of the studies the patients came from databases where the technique used for apoE analysis was PCR-RFLP7,9,11-13. The most commonly used predictors in addition to apoE are age, gender, cognitive function or various imaging parameters such as Cox regression analysis of regions of interest (COX-ROI), analysis of covariance of regions of interest (ANCOVA-ROI) or magnetic resonance imaging and blood biomarkers such as beta-amyloid Aß1-42 or phosphorylated tau protein (p-tau). DISCUSSION: In reference to the evaluation of this technology as a method for apoE genotyping in the diagnosis of familial dysbetalipoproteinemia, it resides as a confirmatory test that is usually performed in conjunction with other lipid profile determinations. In addition to the lack of studies in which qPCR is the method of choice, the only identified study does not include a comparative assay with other genetic or phenotypic techniques for apoE characterisation. In addition to, it should be considered that 10% of familial dysbetalipoproteinemia present an autosomal dominant inheritance pattern, and therefore differ from the typical Ɛ2/Ɛ2 allele pattern, so the use of qPCR may contribute to under-diagnosis this condition. Regarding the use of apoE genotyping by qPCR integrated into a predictive prognostic model for late-onset Alzheimer's disease, no studies were found to support its use. The models identified for this purpose that also include apoE genotyping, although qPCR is not the technique of choice, are models that provide insufficient information to be used in routine clinical practice and to determine the risk of developing late-onset Alzheimer's disease at an individual level. On the one hand, it should be taken into account that both familial dysbetalipoproteinemia and Alzheimer's disease are multifactorial diseases in which the combination of several factors, in addition to carrying a particular genetic pattern, is necessary for the development of the disease. In case of familial dysbetalipoproteinemia, having this type of information could be considered an advantage, mainly because of the existence of an effective pharmacological treatment and/or other preventive measures that could potentially be put in place. On the other hand, in case of late-onset Alzheimer's disease, it is important to keep in mind the ethical and legal considerations associated with the availability of this information linked only to the concept of "susceptibility genes" or "increased risk", given the great social, emotional and economic impact on both the patient and his or her environment, as well as the lack of a therapeutic approach to offer the patient to prevent its development. CONCLUSIONS: The apoE gene plays an important biological role in human lipid metabolism, which has led to the development of different techniques to analyse its polymorphisms and the isoforms generated. There is insufficient scientific evidence to support the use of the qPCR technique as an apoE genotyping method in daily clinical practice or as an added value within a diagnostic algorithm for familial dysbetalipoproteinemia, or as a determination to be incorporated into a prognostic model for early detection of late-onset Alzheimer's disease, compared to other genotyping techniques currently available. In the context an environment of precision medicine, and independently of the genotyping technique used to characterize the apoE gene; the availability of having this information may be relevant for to, in an individualized manner, people with manifestations and/or biochemical lipid alterations, can early adoption therapeutic measures in the case of homozygous familial dysbetalipoproteinemia. For people suspected of having late-onset Alzheimer's disease (60 years of age or older), the implementation of measures to modify the risk factors that may be under the control of the person and their family members, taking into account the resources available in their environment in order to adequately inform the person and access them, if necessary.

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CONTEXT: Dysbetalipoproteinemia (DBL) is a disorder in which remnant lipoproteins accumulate in the plasma due to a genetic apolipoprotein E dysfunction in conjunction with the presence of secondary metabolic factors. An increased risk of both coronary and peripheral vascular disease (PVD) has been observed in these patients in retrospective studies. OBJECTIVE: The primary objective was to compare the incidence of atherosclerotic cardiovascular disease (ASCVD) and PVD in a cohort of patients with DBL compared with normolipidemic controls. As a secondary objective, the incidence of ASCVD and PVD was compared between patients with DBL and patients with familial hypercholesterolemia (FH). METHODS: A total of 221 patients with DBL, 725 patients with FH, and 1481 normolipidemic controls were included in the study. The data were obtained by review of medical records. RESULTS: In patients with DBL, there was an overall excess risk of PVD (hazard ratio [HR] 13.58, 95% CI 4.76-38.75) and ASCVD (HR 3.55, 95% CI 2.17-5.83) (P < .0001) when compared with normolipidemic controls. When compared with patients with FH, an increased risk of PVD (HR 3.89, 95% CI 1.20-12.55, P = .02) was observed in patients with DBL. CONCLUSION: We demonstrated that the risks of ASCVD and PVD in DBL are >3-fold and >13-fold higher, respectively, than normolipidemic controls. Furthermore, the risk of PVD is ∼4-fold higher in DBL than in FH. Adequate screening of DBL is imperative to improve the clinical care of these patients by preventing the development of ASCVD.

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PURPOSE OF REVIEW: In recent years, there has been interest for the development of simplified diagnosis algorithms of dysbetalipoproteinemia (DBL) in order to avoid the complex testing associated with the Fredrickson criteria (reference method). The purpose of this review is to present recent advances in the field of DBL with a focus on screening and diagnosis. RECENT FINDINGS: Recently, two different multi-step algorithms for the diagnosis of DBL have been published and their performance has been compared to the Fredrickson criteria. Furthermore, a recent large study demonstrated that only a minority (38%) of DBL patients are carriers of the E2/E2 genotype and that these individuals presented a more severe phenotype. SUMMARY: The current literature supports the fact that the DBL phenotype is more heterogeneous and complex than previously thought. Indeed, DBL patients can present with either mild or more severe phenotypes that can be distinguished as multifactorial remnant cholesterol disease and genetic apolipoprotein B deficiency. Measurement of apolipoprotein B as well as APOE gene testing are both essential elements in the diagnosis of DBL.

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Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol-enriched remnant lipoproteins. FD is usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow-up, and family counseling.

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PURPOSE OF REVIEW: Lipoprotein (a) [Lp(a)] is a highly atherogenic lipoprotein species. A unique feature of Lp(a) is the strong genetic determination of its concentration. The LPA gene is responsible for up to 90% of the variance in Lp(a), but other genes also have an impact. RECENT FINDINGS: Genome-wide associations studies indicate that the APOE gene, encoding apolipoprotein E (apoE), is the second most important locus modulating Lp(a) concentrations. Population studies clearly show that carriers of the apoE2 variant (ε2) display reduced Lp(a) levels, the lowest concentrations being observed in ε2/ε2 homozygotes. This genotype can lead predisposed adults to develop dysbetalipoproteinemia, a lipid disorder characterized by sharp elevations in cholesterol and triglycerides. However, dysbetalipoproteinemia does not significantly modulate circulating Lp(a). Mechanistically, apoE appears to impair the production but not the catabolism of Lp(a). These observations underline the complexity of Lp(a) metabolism and provide key insights into the pathways governing Lp(a) synthesis and secretion.

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BACKGROUND AND AIMS: Familial dysbetalipoproteinemia (FDBL) is a rare inborn lipid disorder characterized by the formation of abnormal triglyceride- and cholesterol-rich lipoproteins (remnant particles). Patients with FDBL have a high risk for atherosclerotic disease. The effect of PCSK9 inhibition on lipoproteins and its subfractions has not been evaluated in FDBL. METHODS: Three patients (65±7 years, 23±3 kg/m2, 2 females) with FDBL (diagnosed by isoelectrofocusing) and atherosclerosis (coronary and/or cerebro-vascular and/or peripheral arterial disease) resistant or intolerant to statin and fibrate therapy received evolocumab (140mg every 14 days). In addition to a fasting lipid profile (preparative ultracentrifugation), apoB and cholesterol concentrations were determined in 15 lipoprotein-subfractions (density gradient ultracentrifugation; d 1.006-1.21g/ml) before and after 12 weeks of evolocumab treatment. Patients with LDL-hypercholesterolemia (n = 8, 56±8 years, 31±7 kg/m2) and mixed hyperlipidemia (n = 5, 68±12 years, 30±1 kg/m2) also receiving evolocumab for 12 weeks were used for comparison. RESULTS: All patients tolerated PCSK9 inhibition well. PCSK9 inhibitors reduced cholesterol (29-37%), non-HDL-cholesterol (36-50%) and apoB (40-52%) in all patient groups including FDBL. In FDBL, PCSK9 inhibition reduced VLDL-cholesterol and the concentration of apoB containing lipoproteins throughout the whole density spectrum (VLDL, IDL, remnants, LDL). Lipoprotein(a) was decreased in all patient groups to a similar extent. CONCLUSIONS: This indicates that the dominant fraction of apoB-containing lipoproteins is reduced with PCSK9 inhibition, i.e. LDL in hypercholesterolemia and mixed hyperlipidemia, and cholesterol-rich VLDL, remnants and LDL in FDBL. PCSK9 inhibition may be a treatment option in patients with FDBL resistant or intolerant to statin and/or fibrate therapy.

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CONTEXT: Dysbetalipoproteinemia (DBL) is characterized by the accumulation of remnant lipoprotein particles and associated with an increased risk of cardiovascular and peripheral vascular disease (PVD). DBL is thought to be mainly caused by the presence of an E2/E2 genotype of the apolipoprotein E (APOE) gene, in addition to environmental factors. However, there exists considerable phenotypic variability among DBL patients. OBJECTIVE: The objectives were to verify the proportion of DBL subjects, diagnosed using the gold standard Fredrickson criteria, who did not carry E2/E2 and to compare the clinical characteristics of DBL patients with and without E2/E2. METHODS: A total of 12 432 patients with lipoprotein ultracentrifugation as well as APOE genotype or apoE phenotype data were included in this retrospective study. RESULTS: Among the 12 432 patients, 4% (n = 524) were positive for Fredrickson criteria (F+), and only 38% (n = 197) of the F+ individuals were E2/E2. The F+ E2/E2 group had significantly higher remnant cholesterol concentration (3.44 vs 1.89 mmol/L) and had higher frequency of DBL-related xanthomas (24% vs 2%) and floating beta (95% vs 11%) than the F+ non-E2/E2 group (P < 0.0001). The F+ E2/E2 group had an independent higher risk of PVD (OR 11.12 [95% CI 1.87-66.05]; P = 0.008) events compared with the F+ non-E2/E2 group. CONCLUSION: In the largest cohort of DBL worldwide, we demonstrated that the presence of E2/E2 was associated with a more severe DBL phenotype. We suggest that 2 DBL phenotypes should be distinguished: the multifactorial remnant cholesterol disease and the genetic apoE deficiency disease.

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INTRODUCTION: Primary dyslipidemias are inherited disorders in plasma lipoprotein metabolism that lead to serious cardiovascular and other complications. The Japanese Ministry of Health, Labor and Welfare (MHLW) covers medical expenses, under the Research Program on Rare and Intractable Diseases, for homozygous familial hypercholesterolemia (FH), familial chylomicronemia, sitosterolemia, cerebrotendinous xanthomatosis, lecithin:cholesterol acyltransferase deficiency, Tangier disease, and abetalipoproteinemia. Apolipoprotein A1 deficiency, heterozygous FH, and type III hyperlipoproteinemia are covered by the MHLW Pediatric Chronic Disease Program. Heterozygous FH and type III hyperlipoproteinemia are also important for their relatively common prevalence and, accordingly, high impact on Japanese public health by significant contribution to the overall prevalence of cardiovascular diseases. Therefore, a systemic survey of these diseases is mandatory to estimate their actual situation, such as prevalence, clinical manifestations, and prognoses among the Japanese population. The impact of these rare and intractable diseases on cardiovascular and other complications will likely be higher among Japanese people than other ethnicities because the general Japanese population has many cardioprotective aspects. The current study intends to conduct a multicenter registry of these diseases to assess their demographics and clinical features comprehensively. METHODS AND ANALYSIS: The Prospective Registry Study of Primary Dyslipidemia is a registry-based prospective, observational, multicenter cohort study in Japan, enrolling patients who fulfill the Japanese clinical criteria of the primary dyslipidemias listed above, from 26 participating institutes from August 2015 to March 2023. A total of 1,000 patients will be enrolled in the study and followed for 10 years. Clinical parameters are collected, including physical and laboratory findings, genetic analysis, drugs, lifestyle management, and clinical events, especially cardiovascular events. The primary endpoint of this study is the new onset of cardiovascular disease and acute pancreatitis, and the secondary endpoint is death from any causes. ETHICS AND DISSEMINATION: This study complies with the Declaration of Helsinki, the Ethical Guidelines for Medical and Health Research Involving Human Subjects, and all other applicable laws and guidelines in Japan. The institutional review boards have approved this study protocol at all participating institutes. The final results are to be published at appropriate international conferences and in peer-reviewed journals.

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BACKGROUND: Guideline recommendations for the management of lipids in patients at risk for cardiovascular disease is largely based on low-density lipoprotein cholesterol (LDL-C) concentration. LDL-C is commonly calculated by the Friedewald equation, which has many limitations. The National Institutes of Health (NIH) equation better estimates LDL-C, particularly in patients with hypertriglyceridemia and/or low LDL-C. We validated the NIH LDL-C equation at the first Canadian clinical laboratory to implement this equation. METHODS: A total of 3161 lipid ultracentrifugation results from a specialized lipid cohort of 2836 patients were included. LDL-C was calculated using the NIH and Friedewald equations and compared to LDL-C measured by ultracentrifugation. We determined the accuracy of these equations at treatment thresholds and developed NIH equation restriction criteria to ensure only accurate results are reported. RESULTS: Ultracentrifugation LDL-C more strongly correlated with NIH-calculated LDL-C (r2 = 0.889) than Friedewald-calculated LDL-C (r2 = 0.807) and resulted in fewer non-sensical negative LDL-C values. The correlation for NIH-calculated LDL-C improved to r2 = 0.975 after applying our restriction criteria. The NIH equation showed equivalent or superior concordance with ultracentrifugation at treatment thresholds. The LDL-C mean absolute difference increased with increasing TG and decreasing LDL-C concentrations, although the NIH equation was more robust under both conditions. CONCLUSIONS: We validated the NIH equation against ultracentrifugation in a cohort with a wide lipid concentration range, which supported its superiority over the Friedewald equation. We recommend clinical implementing the NIH equation for all patients except those with type III hyperlipoproteinemia or TG > 9.04 mmol/L, with an LDL-C lower reporting limit of <0.50 mmol/L.

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Dysbetalipoproteinemia (DBL) is an uncommon condition characterized by a mixed hyperlipidemia due to accumulation of remnant lipoproteins and is highly atherogenic. Typically, DBL is an autosomal recessive condition requiring an additional metabolic stress with reduced apolipoprotein E (apoE) function. However, DBL is also described in patients with multiple myeloma without the characteristic apoE2/E2 mutation seen in familial DBL. Although the underlying pathogenesis in these cases is not fully characterized, it is thought to occur due to interference with apoE function by antibodies produced from clonal plasma cells. Such cases are referred to as hyperlipidemic myeloma (HLM) and have rarely been described in the literature. To our knowledge there is no prior description of HLM in HIV positive patients in Africa. We describe a case of HLM in an African woman with underlying HIV infection who presented with phenotypic and biochemical features of DBL that responded poorly to lipid lowering therapy.

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PURPOSE OF REVIEW: The functions, genetic variations and impact of apolipoprotein E on lipoprotein metabolism in general are placed in the context of clinical practice dealing with moderate dyslipidaemia as well as dysbetalipoproteinemia, a highly atherogenic disorder and lipoprotein glomerulopathy. RECENT FINDINGS: Additional variants of apolipoprotein E and participation of apolipoprotein E in inflammation are of interest. The mostly favourable effects of apolipoprotein E2 as well as the atherogenic nature of apolipoproteinE4, which has an association with cognitive impairment, are confirmed. The contribution of remnant lipoproteins of triglyceride-rich lipoproteins, of which dysbetalipoproteinemia represents an extreme, is explored in atherosclerosis. Mimetic peptides may present new therapeutic approaches. Apolipoprotein E is an important determinant of the lipid profile and cardiovascular health in the population at large and can precipitate dysbetalipoproteinemia and glomerulopathy. Awareness of apolipoprotein E polymorphisms should improve medical care.

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Dysbetalipoproteinaemia (or type III hyperlipoproteinaemia) is a severe mixed hyperlipidaemia resulting from the accumulation of remnant chylomicron and VLDL particles in plasma, also called ß-VLDL. It is caused by a defect in the recognition by hepatic LDL and lipoprotein receptor-related protein (LRP) of ß-VLDL. Mutations in the APOE gene, especially in subjects homozygous for the ɛ2/ɛ2 allele, are responsible for this lack of receptor recognition. Dysbetalipoproteinaemia represents 2-5% of the mixed dyslipidaemias seen in Lipid Units, is highly atherogenic and predisposes to diffuse atheromatosis, either coronary, peripheral vascular, or carotid, so early diagnosis and treatment is necessary. The presence of hypertriglyceridaemia, with non-HDL cholesterol/apolipoprotein B ratios>1.43 (in mg/dL) followed by APOE genotyping is the method of choice in the diagnosis of dysbetalipoproteinaemia. It is a dyslipidaemia that responds well to hygienic-dietary treatment, although the combination of statin and fenofibrate is often necessary to achieve optimal control.

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