Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm

Purpose Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. Methods We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. Results We identified five functional variants inTHSD4of which two heterozygous variants lead to a premature termination codon.THSD4encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. TheTHSD4variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils.Thsd4(+/-)mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying aTHSD4variant and fromThsd4(+/-)mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. Conclusion These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies

Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome

Background: The low-density lipoprotein receptor (LDLR) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease.Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of datasets on gene expression and variants in human populations.Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR. The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in non-transfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in non-alcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and three rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared to overexpression of wild type RBM25, overexpression of the three rare RBM25 mutants in Huh-7 cells led to lower LDL uptake.Conclusions: We identified a novel mechanism of post-transcriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.</p

Rôle de PCSK9 et des variations du gène APOE dans la modulation de l’athérosclérose : approches moléculaires et physiopathologiques

According to the World Health Organization, cardiovascular diseases (CVD) are the leading cause of death in the world with more than 30% of cases. Atherosclerosis is one of the main causes of CVD. It consists of the formation of atherosclerotic plaques within the arterial wall of which cholesterol, smooth muscle cells (SMC) and SMC-derived foam are main components. Hypercholesterolemia is one of the major risk factors for atherosclerosis, affecting nearly 20% of the population in France. Autosomal dominant hypercholesterolemia (ADH) is characterized by abnormally high plasma levels of total cholesterol and Low Density Lipoprotein (LDL)- cholesterol. It is caused by genetic defects in four main genes: LDLR, APOB, PCSK9 and APOE. The main objective of this thesis is to identify new actors of the development of atherosclerosis and CVD. The first part of this work consists in studying the involvement of the APOE gene in ADH in France, through the "National Research Network on Hypercholesterolemia". The second part consists in studying the role played by PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) in the development of human atheroma within the vascular wall independently of its well-established role on the LDL receptor at the hepatic level. This research project has allowed the sequencing of the APOE gene in French ADH probands without known mutations in the LDLR/APOB/PCSK9 genes, in order to establish the spectrum of APOE mutations in France. 31 rare variants were identified in 76 probands, including five already described in primary dyslipidemia. However, the complexity of the function of apoE in lipid homeostasis makes the interpretation of the novel variants difficult and dependent on many factors. Thus, screening of APOE should be included in the routine of the diagnosis of ADH in order to improve the prognosis and the care management of patients and their family members. Regarding the role of PCSK9 in atherosclerosis, studies on human aortic tissues have shown that plasma PCSK9 penetrates the arterial wall where it is detected in intimal SMCs of atherosclerotic vessels. Studies on primary cultures of human SMCs have shown that they do not express PCSK9 and that PCSK9 seems to interact with scavenger receptors expressed by these cells such as LOX1. The identification of a direct role of plasma PCSK9 in human atheroma development would extend the spectrum of application of anti-PCSK9 monoclonal antibodies to the prevention of atherosclerosis. In conclusion, genetic studies associated with functional studies allow the identification of new actors of atherosclerosis and its risk factors, a better understanding of its physiopathological mechanisms and the identification of new therapeutic targets.Selon l'Organisation Mondiale de la Santé, les maladies cardiovasculaires (MCV) sont la première cause de mortalité au monde avec plus de 30% des cas. L'athérosclérose est l'une des principales causes de MCV. Elle consiste en la formation au niveau de la paroi artérielle de plaques d'athérome dont le cholestérol, les cellules musculaires lisses (CML) et les cellules spumeuses qui en dérivent sont parmi les principaux constituants. L'hypercholestérolémie est l'un des facteurs de risque majeurs de l'athérosclérose, elle touche près de 20% de la population dans le monde. L'hypercholestérolémie à transmission autosomique dominante (ADH) est caractérisée par des taux plasmatiques anormalement élevés de cholestérol total et de cholestérol lié aux particules LDL (low density liporpotein). Elle est due à des défauts génétiques au niveau de quatre gènes principaux : LDLR, APOB, PCSK9 et, APOE. L'objectif principal de cette thèse est d'identifier de nouveaux acteurs du développement de l'athérosclérose et des MCV. La première partie de ce travail consiste à étudier l'implication du gène APOE dans l'ADH en France, et ceci à travers « le Réseau National de Recherche sur les Hypercholestérolémies ». Quant à la deuxième partie de ce travail, elle consiste, grâce à la biobanque cardiovasculaire mise en place dans l'unité, à étudier le rôle joué par PCSK9 (Proprotein Convertase Subtilysin Kexin type 9) dans le développement de l'athérome au niveau de la paroi vasculaire indépendamment de son rôle bien établi sur le récepteur des LDL au niveau hépatique. Ce projet de recherche a permis par le séquençage du gène APOE chez des proposants ADH sans mutation connue dans les gènes LDLR/APOB/PCSK9, d'établir le spectre de mutations APOE dans une cohorte de proposants ADH en France. 31 variants rares ont été identifiés chez 76 proposants dont 5 déjà impliqués dans des dyslipidémies. Cependant, la complexité de la fonction de l'apoE dans l'homéostasie lipidique rend l'interprétation des nouveaux variants trouvés difficile et dépendante de nombreux facteurs. Le dépistage des variants APOE devrait être inclus dans la routine de diagnostic de l'ADH afin d'améliorer le pronostic et la prise en charge des patients et de leurs apparentés. En ce qui concerne le rôle de PCSK9 dans l'athérosclérose, les études sur des tissus aortiques humains ont montré que PCSK9 plasmatique pénètre dans la paroi artérielle où elle est détectée dans les CML au niveau de l'intima, d'autant plus que la paroi est athéromateuse. Les études sur des cultures primaires de CML humaines ont montré que celles-ci n'expriment pas PCSK9 et que PCSK9 semble interagir avec certains récepteurs scavengers exprimés par ces cellules tels que LOX1. La mise en évidence d'une telle fonction de PCSK9 plasmatique permettrait d'élargir le spectre d'application des anticorps monoclonaux anti-PCSK9 à la prévention du développement de l'athérosclérose. Ainsi, les études génétiques associées à des études fonctionnelles et mécanistiques permet la détermination de nouveaux acteurs de l'athérosclérose et ses facteurs de risque, une meilleure compréhension de ses mécanismes physiopathologiques et l'identification de nouvelles cibles thérapeutiques

Role of PCSK9 and APOE gene variants in the modulation of atherosclerosis : molecular and pathophysiological approaches

Selon l'Organisation Mondiale de la Santé, les maladies cardiovasculaires (MCV) sont la première cause de mortalité au monde avec plus de 30% des cas. L'athérosclérose est l'une des principales causes de MCV. Elle consiste en la formation au niveau de la paroi artérielle de plaques d'athérome dont le cholestérol, les cellules musculaires lisses (CML) et les cellules spumeuses qui en dérivent sont parmi les principaux constituants. L'hypercholestérolémie est l'un des facteurs de risque majeurs de l'athérosclérose, elle touche près de 20% de la population dans le monde. L'hypercholestérolémie à transmission autosomique dominante (ADH) est caractérisée par des taux plasmatiques anormalement élevés de cholestérol total et de cholestérol lié aux particules LDL (low density liporpotein). Elle est due à des défauts génétiques au niveau de quatre gènes principaux : LDLR, APOB, PCSK9 et, APOE. L'objectif principal de cette thèse est d'identifier de nouveaux acteurs du développement de l'athérosclérose et des MCV. La première partie de ce travail consiste à étudier l'implication du gène APOE dans l'ADH en France, et ceci à travers « le Réseau National de Recherche sur les Hypercholestérolémies ». Quant à la deuxième partie de ce travail, elle consiste, grâce à la biobanque cardiovasculaire mise en place dans l'unité, à étudier le rôle joué par PCSK9 (Proprotein Convertase Subtilysin Kexin type 9) dans le développement de l'athérome au niveau de la paroi vasculaire indépendamment de son rôle bien établi sur le récepteur des LDL au niveau hépatique. Ce projet de recherche a permis par le séquençage du gène APOE chez des proposants ADH sans mutation connue dans les gènes LDLR/APOB/PCSK9, d'établir le spectre de mutations APOE dans une cohorte de proposants ADH en France. 31 variants rares ont été identifiés chez 76 proposants dont 5 déjà impliqués dans des dyslipidémies. Cependant, la complexité de la fonction de l'apoE dans l'homéostasie lipidique rend l'interprétation des nouveaux variants trouvés difficile et dépendante de nombreux facteurs. Le dépistage des variants APOE devrait être inclus dans la routine de diagnostic de l'ADH afin d'améliorer le pronostic et la prise en charge des patients et de leurs apparentés. En ce qui concerne le rôle de PCSK9 dans l'athérosclérose, les études sur des tissus aortiques humains ont montré que PCSK9 plasmatique pénètre dans la paroi artérielle où elle est détectée dans les CML au niveau de l'intima, d'autant plus que la paroi est athéromateuse. Les études sur des cultures primaires de CML humaines ont montré que celles-ci n'expriment pas PCSK9 et que PCSK9 semble interagir avec certains récepteurs scavengers exprimés par ces cellules tels que LOX1. La mise en évidence d'une telle fonction de PCSK9 plasmatique permettrait d'élargir le spectre d'application des anticorps monoclonaux anti-PCSK9 à la prévention du développement de l'athérosclérose. Ainsi, les études génétiques associées à des études fonctionnelles et mécanistiques permet la détermination de nouveaux acteurs de l'athérosclérose et ses facteurs de risque, une meilleure compréhension de ses mécanismes physiopathologiques et l'identification de nouvelles cibles thérapeutiques.According to the World Health Organization, cardiovascular diseases (CVD) are the leading cause of death in the world with more than 30% of cases. Atherosclerosis is one of the main causes of CVD. It consists of the formation of atherosclerotic plaques within the arterial wall of which cholesterol, smooth muscle cells (SMC) and SMC-derived foam are main components. Hypercholesterolemia is one of the major risk factors for atherosclerosis, affecting nearly 20% of the population in France. Autosomal dominant hypercholesterolemia (ADH) is characterized by abnormally high plasma levels of total cholesterol and Low Density Lipoprotein (LDL)- cholesterol. It is caused by genetic defects in four main genes: LDLR, APOB, PCSK9 and APOE. The main objective of this thesis is to identify new actors of the development of atherosclerosis and CVD. The first part of this work consists in studying the involvement of the APOE gene in ADH in France, through the "National Research Network on Hypercholesterolemia". The second part consists in studying the role played by PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) in the development of human atheroma within the vascular wall independently of its well-established role on the LDL receptor at the hepatic level. This research project has allowed the sequencing of the APOE gene in French ADH probands without known mutations in the LDLR/APOB/PCSK9 genes, in order to establish the spectrum of APOE mutations in France. 31 rare variants were identified in 76 probands, including five already described in primary dyslipidemia. However, the complexity of the function of apoE in lipid homeostasis makes the interpretation of the novel variants difficult and dependent on many factors. Thus, screening of APOE should be included in the routine of the diagnosis of ADH in order to improve the prognosis and the care management of patients and their family members. Regarding the role of PCSK9 in atherosclerosis, studies on human aortic tissues have shown that plasma PCSK9 penetrates the arterial wall where it is detected in intimal SMCs of atherosclerotic vessels. Studies on primary cultures of human SMCs have shown that they do not express PCSK9 and that PCSK9 seems to interact with scavenger receptors expressed by these cells such as LOX1. The identification of a direct role of plasma PCSK9 in human atheroma development would extend the spectrum of application of anti-PCSK9 monoclonal antibodies to the prevention of atherosclerosis. In conclusion, genetic studies associated with functional studies allow the identification of new actors of atherosclerosis and its risk factors, a better understanding of its physiopathological mechanisms and the identification of new therapeutic targets

Rôle de PCSK9 et des variations du gène APOE dans la modulation de l’athérosclérose : approches moléculaires et physiopathologiques

According to the World Health Organization, cardiovascular diseases (CVD) are the leading cause of death in the world with more than 30% of cases. Atherosclerosis is one of the main causes of CVD. It consists of the formation of atherosclerotic plaques within the arterial wall of which cholesterol, smooth muscle cells (SMC) and SMC-derived foam are main components. Hypercholesterolemia is one of the major risk factors for atherosclerosis, affecting nearly 20% of the population in France. Autosomal dominant hypercholesterolemia (ADH) is characterized by abnormally high plasma levels of total cholesterol and Low Density Lipoprotein (LDL)- cholesterol. It is caused by genetic defects in four main genes: LDLR, APOB, PCSK9 and APOE. The main objective of this thesis is to identify new actors of the development of atherosclerosis and CVD. The first part of this work consists in studying the involvement of the APOE gene in ADH in France, through the "National Research Network on Hypercholesterolemia". The second part consists in studying the role played by PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) in the development of human atheroma within the vascular wall independently of its well-established role on the LDL receptor at the hepatic level. This research project has allowed the sequencing of the APOE gene in French ADH probands without known mutations in the LDLR/APOB/PCSK9 genes, in order to establish the spectrum of APOE mutations in France. 31 rare variants were identified in 76 probands, including five already described in primary dyslipidemia. However, the complexity of the function of apoE in lipid homeostasis makes the interpretation of the novel variants difficult and dependent on many factors. Thus, screening of APOE should be included in the routine of the diagnosis of ADH in order to improve the prognosis and the care management of patients and their family members. Regarding the role of PCSK9 in atherosclerosis, studies on human aortic tissues have shown that plasma PCSK9 penetrates the arterial wall where it is detected in intimal SMCs of atherosclerotic vessels. Studies on primary cultures of human SMCs have shown that they do not express PCSK9 and that PCSK9 seems to interact with scavenger receptors expressed by these cells such as LOX1. The identification of a direct role of plasma PCSK9 in human atheroma development would extend the spectrum of application of anti-PCSK9 monoclonal antibodies to the prevention of atherosclerosis. In conclusion, genetic studies associated with functional studies allow the identification of new actors of atherosclerosis and its risk factors, a better understanding of its physiopathological mechanisms and the identification of new therapeutic targets.Selon l'Organisation Mondiale de la Santé, les maladies cardiovasculaires (MCV) sont la première cause de mortalité au monde avec plus de 30% des cas. L'athérosclérose est l'une des principales causes de MCV. Elle consiste en la formation au niveau de la paroi artérielle de plaques d'athérome dont le cholestérol, les cellules musculaires lisses (CML) et les cellules spumeuses qui en dérivent sont parmi les principaux constituants. L'hypercholestérolémie est l'un des facteurs de risque majeurs de l'athérosclérose, elle touche près de 20% de la population dans le monde. L'hypercholestérolémie à transmission autosomique dominante (ADH) est caractérisée par des taux plasmatiques anormalement élevés de cholestérol total et de cholestérol lié aux particules LDL (low density liporpotein). Elle est due à des défauts génétiques au niveau de quatre gènes principaux : LDLR, APOB, PCSK9 et, APOE. L'objectif principal de cette thèse est d'identifier de nouveaux acteurs du développement de l'athérosclérose et des MCV. La première partie de ce travail consiste à étudier l'implication du gène APOE dans l'ADH en France, et ceci à travers « le Réseau National de Recherche sur les Hypercholestérolémies ». Quant à la deuxième partie de ce travail, elle consiste, grâce à la biobanque cardiovasculaire mise en place dans l'unité, à étudier le rôle joué par PCSK9 (Proprotein Convertase Subtilysin Kexin type 9) dans le développement de l'athérome au niveau de la paroi vasculaire indépendamment de son rôle bien établi sur le récepteur des LDL au niveau hépatique. Ce projet de recherche a permis par le séquençage du gène APOE chez des proposants ADH sans mutation connue dans les gènes LDLR/APOB/PCSK9, d'établir le spectre de mutations APOE dans une cohorte de proposants ADH en France. 31 variants rares ont été identifiés chez 76 proposants dont 5 déjà impliqués dans des dyslipidémies. Cependant, la complexité de la fonction de l'apoE dans l'homéostasie lipidique rend l'interprétation des nouveaux variants trouvés difficile et dépendante de nombreux facteurs. Le dépistage des variants APOE devrait être inclus dans la routine de diagnostic de l'ADH afin d'améliorer le pronostic et la prise en charge des patients et de leurs apparentés. En ce qui concerne le rôle de PCSK9 dans l'athérosclérose, les études sur des tissus aortiques humains ont montré que PCSK9 plasmatique pénètre dans la paroi artérielle où elle est détectée dans les CML au niveau de l'intima, d'autant plus que la paroi est athéromateuse. Les études sur des cultures primaires de CML humaines ont montré que celles-ci n'expriment pas PCSK9 et que PCSK9 semble interagir avec certains récepteurs scavengers exprimés par ces cellules tels que LOX1. La mise en évidence d'une telle fonction de PCSK9 plasmatique permettrait d'élargir le spectre d'application des anticorps monoclonaux anti-PCSK9 à la prévention du développement de l'athérosclérose. Ainsi, les études génétiques associées à des études fonctionnelles et mécanistiques permet la détermination de nouveaux acteurs de l'athérosclérose et ses facteurs de risque, une meilleure compréhension de ses mécanismes physiopathologiques et l'identification de nouvelles cibles thérapeutiques

APOE gene variants in primary dyslipidemia

International audienceApolipoprotein E (apoE) is a major apolipoprotein involved in lipoprotein metabolism. It is a polymorphic protein and different isoforms are associated with variations in lipid and lipoprotein levels and thus cardiovascular risk. The isoform apoE4 is associated with an increase in LDL-cholesterol levels and thus a higher cardiovascular risk compared to apoE3. Whereas, apoE2 is associated with a mild decrease in LDL-cholesterol levels. In the presence of other risk factors, apoE2 homozygotes could develop type III hyperlipoproteinemia (familial dysbetalipoproteinemia or FD), an atherogenic disorder characterized by an accumulation of remnants of triglyceride-rich lipoproteins. Several rare APOE gene variants were reported in different types of dyslipidemias including FD, familial combined hyperlipidemia (FCH), lipoprotein glomerulopathy and bona fide autosomal dominant hypercholesterolemia (ADH). ADH is characterized by elevated LDL-cholesterol levels leading to coronary heart disease, and due to molecular alterations in three main genes: LDLR, APOB and PCSK9. The identification of the APOE-p.Leu167del variant as the causative molecular element in two different ADH families, paved the way to considering APOE as a candidate gene for ADH. Due to non mendelian interacting factors, common genetic and environmental factors and perhaps epigenetics, clinical presentation of lipid disorders associated with APOE variants often strongly overlap. More studies are needed to determine the spectrum of APOE implication in each of the diseases, notably ADH, in order to improve clinical and genetic diagnosis, prognosis and patient management. The purpose of this review is to comment on these APOE variants and on the molecular and clinical overlaps between dyslipidemias

Circulating PCSK9 Linked to Dyslipidemia in Lebanese Schoolchildren

In adults, elevated levels of circulating Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) have been associated with increased Low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and worse cardiovascular outcomes. However, few studies analyzed the relation between PCSK9 and lipid parameters in pediatric populations. The aim of our study is to evaluate the distribution and the correlation of serum PCSK9 levels with lipid parameters in a sample of Lebanese school children. Using an immunofluorescence assay, we measured serum PCSK9 levels in 681 school children recruited from ten public and private Lebanese schools. We analyzed the association between PCSK9 and age, sex, Body Mass Index (BMI), and lipid parameters (total cholesterol (TC), LDL-C, TG, High-density lipoprotein cholesterol (HDL-C), non-HDL-C, and lipoprotein (a) (Lp(a)). Serum PCSK9 levels were significantly correlated with TC, LDL-C, and non-HDL-C (p value p values = 0.0012, 0.0002, 0.001, respectively). No significant gender differences in PCSK9 were found. In addition, no significant associations between PCSK9 and both age and BMI percentiles were observed. In girls, no difference in PCSK9 values was observed according to menarche while in boys, testosterone levels were not significantly associated with PCSK9. Serum PCSK9 levels were significantly correlated with TC, LDL-C, and non-HDL-C levels. Further studies are needed to find if PCSK9 measurements have an additional value to predict future cardiovascular outcomes in pediatric populations

Identification of a variant in apob gene as a major cause of hypobetalipoproteinemia in lebanese families

International audienceFamilial hypobetalipoproteinemia (FHBL) is a codominant genetic disorder characterized by reduced plasma levels of low-density lipoprotein cholesterol and apolipoprotein B. To our knowl-edge, no study on FHBL in Lebanon and the Middle East region has been reported. Therefore, we conducted genetic studies in unrelated families and probands of Lebanese origin presenting with FHBL, in order to identify the causes of this disease. We found that 71% of the recruited probands and their affected relatives were heterozygous for the p.(Arg490Trp) variant in the APOB gene. Haplotype analysis showed that these patients presented the same mutant haplotype. Moreover, there was a decrease in plasma levels of PCSK9 in affected individuals compared to the non-affected and a significant positive correlation between circulating PCSK9 and ApoB levels in all studied probands and their family members. Some of the p.(Arg490Trp) carriers suffered from diabetes, hepatic steatosis or neurological problems. In conclusion, the p.(Arg490Trp) pathogenic variant seems a cause of FHBL in patients from Lebanese origin, accounting for approximately 70% of the probands with FHBL presumably as a result of a founder mutation in Lebanon. This study is crucial to guide the early diagnosis, management and prevention of the associated complications of this disease

Additive Effect of APOE Rare Variants on the Phenotype of Familial Hypercholesterolemia

International audienceBackground: Autosomal dominant hypercholesterolemia (ADH) is due to deleterious variants in LDLR, APOB, or PCSK9 genes. Double heterozygote for these genes induces a more severe phenotype. More recently, a new causative variant of heterozygous ADH was identified in APOE. Here we study the phenotype of 21 adult patients, double heterozygotes for rare LDLR and rare APOE variants (LDLR+APOE) in a national wide French cohort. Methods: LDLR, APOB, PCSK9, and APOE genes were sequenced in 5743 probands addressed for ADH genotyping. The lipid profile and occurrence of premature atherosclerotic cardiovascular diseases were compared between the LDLR+APOE carriers (n=21) and the carriers of the same LDLR causative variants alone (n=22). Results: The prevalence of LDLR+APOE carriers in this French ADH cohort is 0.4%. Overall, LDL (low-density lipoprotein)-cholesterol concentrations were 23% higher in LDLR+APOE patients than in LDLR patients (9.14±2.51 versus 7.43±1.59 mmol/L, P=0.0221). When only deleterious or probably deleterious variants were considered, the LDL-cholesterol concentrations were 46% higher in LDLR+APOE carriers than in LDLR carriers (10.83±3.45 versus 7.43±1.59 mmol/L, P=0.0270). Two patients exhibited a homozygous familial hypercholesterolemia phenotype (LDL-cholesterol >13 mmol/L). Premature atherosclerotic cardiovascular disease was more common in LDLR+APOE patients than in LDLR carriers (70% versus 30%, P=0.026). Conclusions: Although an incomplete penetrance should be taken into account for APOE variant classification, these results suggest an additive effect of deleterious APOE variants on ADH phenotype highlighting the relevance of APOE sequencing

APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

International audiencePrimary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9, APOB, and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR, PCSK9, or APOB. Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL