Search

Your search keyword '"Yara Abou-Khalil"' showing total 14 results
Start Over Author "Yara Abou-Khalil"
14 results on '"Yara Abou-Khalil"'

1. Low circulating PCSK9 levels in LPL homozygous children with chylomicronemia syndrome in a syrian refugee family in Lebanon

Author

Carine Ayoub, Yara Azar, Dina Maddah, Youmna Ghaleb, Sandy Elbitar, Yara Abou-Khalil, Selim Jambart, Mathilde Varret, Catherine Boileau, Petra El Khoury, and Marianne Abifadel

Subjects
chylomicronemia syndrome, type 1 hyperlipoproteinemia, LPL gene, triglycerides, Lebanon, Syria, Genetics, QH426-470
Abstract

Familial chylomicronemia syndrome is a rare autosomal recessive disorder of lipoprotein metabolism characterized by the presence of chylomicrons in fasting plasma and an important increase in plasma triglycerides (TG) levels that can exceed 22.58 mmol/l. The disease is associated with recurrent episodes of abdominal pain and pancreatitis, eruptive cutaneous xanthomatosis, lipemia retinalis, and hepatosplenomegaly. A consanguineous Syrian family who migrated to Lebanon was referred to our laboratory after perceiving familial chylomicronemia syndrome in two children. The LPL and PCSK9 genes were sequenced and plasma PCSK9 levels were measured. Sanger sequencing of the LPL gene revealed the presence of the p.(Val227Phe) pathogenic variant in exon 5 at the homozygous state in the two affected children, and at the heterozygous state in the other recruited family members. Interestingly, PCSK9 levels in homozygous carriers of the p.(Val227Phe) were ≈50% lower than those in heterozygous carriers of the variant (p-value = 0.13) and ranged between the 5th and the 7.5th percentile of PCSK9 levels in a sample of Lebanese children of approximately the same age group. Moreover, this is the first reported case of individuals carrying simultaneously an LPL pathogenic variant and PCSK9 variants, the L10 and L11 leucine insertion, which can lower and raise low-density lipoprotein cholesterol (LDL-C) levels respectively. TG levels fluctuated concomitantly between the two children, were especially high following the migration from a country to another, and were reduced under a low-fat diet. This case is crucial to raise public awareness on the risks of consanguineous marriages to decrease the emergence of inherited autosomal recessive diseases. It also highlights the importance of the early diagnosis and management of these diseases to prevent serious complications, such as recurrent pancreatitis in the case of familial hyperchylomicronemia.

Published
2022
Full Text
View/download PDF

2. Whole Exome/Genome Sequencing Joint Analysis of a Family with Oligogenic Familial Hypercholesterolemia

Author

Youmna Ghaleb, Sandy Elbitar, Anne Philippi, Petra El Khoury, Yara Azar, Miangaly Andrianirina, Alexia Loste, Yara Abou-Khalil, Gaël Nicolas, Marie Le Borgne, Philippe Moulin, Mathilde Di-Filippo, Sybil Charrière, Michel Farnier, Cécile Yelnick, Valérie Carreau, Jean Ferrières, Jean-Michel Lecerf, Alexa Derksen, Geneviève Bernard, Marie-Soleil Gauthier, Benoit Coulombe, Dieter Lütjohann, Bertrand Fin, Anne Boland, Robert Olaso, Jean-François Deleuze, Jean-Pierre Rabès, Catherine Boileau, Marianne Abifadel, and Mathilde Varret

Subjects
autosomal dominant hypercholesterolemia, linkage analysis, next-generation sequencing, LDL uptake, CYP7A1, LRP6, Microbiology, QR1-502
Abstract

Autosomal Dominant Hypercholesterolemia (ADH) is a genetic disorder caused by pathogenic variants in LDLR, APOB, PCSK9 and APOE genes. We sought to identify new candidate genes responsible for the ADH phenotype in patients without pathogenic variants in the known ADH-causing genes by focusing on a French family with affected and non-affected members who presented a high ADH polygenic risk score (wPRS). Linkage analysis, whole exome and whole genome sequencing resulted in the identification of variants p.(Pro398Ala) in CYP7A1, p.(Val1382Phe) in LRP6 and p.(Ser202His) in LDLRAP1. A total of 6 other variants were identified in 6 of 160 unrelated ADH probands: p.(Ala13Val) and p.(Aps347Asn) in CYP7A1; p.(Tyr972Cys), p.(Thr1479Ile) and p.(Ser1612Phe) in LRP6; and p.(Ser202LeufsTer19) in LDLRAP1. All six probands presented a moderate wPRS. Serum analyses of carriers of the p.(Pro398Ala) variant in CYP7A1 showed no differences in the synthesis of bile acids compared to the serums of non-carriers. Functional studies of the four LRP6 mutants in HEK293T cells resulted in contradictory results excluding a major effect of each variant alone. Within the family, none of the heterozygous for only the LDLRAP1 p.(Ser202His) variant presented ADH. Altogether, each variant individually does not result in elevated LDL-C; however, the oligogenic combination of two or three variants reveals the ADH phenotype.

Published
2022
Full Text
View/download PDF

3. Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families

Author

Carine Ayoub, Yara Azar, Yara Abou-Khalil, Youmna Ghaleb, Sandy Elbitar, Georges Halaby, Selim Jambart, Marie-Hélène Gannagé-Yared, Cesar Yaghi, Carole Saade Riachy, Ralph El Khoury, Jean-Pierre Rabès, Mathilde Varret, Catherine Boileau, Petra El Khoury, and Marianne Abifadel

Subjects
familial hypobetalipoproteinemia, low-density lipoprotein cholesterol, APOB gene, PCSK9, non-alcoholic fatty liver, diabetes, Microbiology, QR1-502
Abstract

Familial hypobetalipoproteinemia (FHBL) is a codominant genetic disorder characterized by reduced plasma levels of low-density lipoprotein cholesterol and apolipoprotein B. To our knowledge, 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.

Published
2021
Full Text
View/download PDF

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

Author

Oriane Marmontel, Yara Abou-Khalil, Olivier Bluteau, Bertrand Cariou, Valérie Carreau, Sybil Charrière, Eleonore Divry, Antonio Gallo, Philippe Moulin, François Paillard, Noel Peretti, Jean-Pierre Rabès, Mathilde Varret, Alain Carrié, and Mathilde Di Filippo

Subjects
Cardiology and Cardiovascular Medicine
Abstract

Background: 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.

Published
2023
Full Text
View/download PDF

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

Author

Olivier Milleron, Marie Paule Jacob, Benoît Ho-Tin-Noé, Marjolijn Renard, Nadine Hanna, Guillaume Jondeau, Laurent Gouya, Marie Sylvie Gross, Sebastien Dupont, Sandy Elbitar, Sébastien Gaertner, Marianne Abifadel, Jeremie Jonquet, Ketty Kessler, Bertrand Isidor, Catherine Boileau, Yves Alembik, Kiyotoshi Sekiguchi, Dianna M. Milewicz, Laurent Tosolini, Mathilde Varret, Mélodie Aubart, Yara Abou Khalil, Youmna Ghaleb, Dongchuan Guo, Jean-Baptiste Michel, Maud Langeois, Louise Benarroch, Ko Tsutsui, Vincenzo Dattilo, Pauline Arnaud, Julie De Backer, Carine Le Goff, Lynn Y. Sakai, and Petra El Khoury

Subjects
0301 basic medicine, Marfan syndrome, diagnosis, Fibrillin-1, FIBRONECTIN, thoracic aortic aneurysm, THSD4, 030105 genetics & heredity, Biology, Thoracic aortic aneurysm, DISSECTIONS, DISEASE, Article, Pathogenesis, Mice, 03 medical and health sciences, ADAMTSL6, medicine.artery, Medicine and Health Sciences, medicine, Animals, Humans, Thoracic aorta, Genetics(clinical), Exome, FBN1, Genetics (clinical), Exome sequencing, Genetics, Aortic Aneurysm, Thoracic, MUTATIONS, ADAMTS, MOUSE MODEL, FIBRILLIN-1, medicine.disease, GENE, MARFAN-SYNDROME, TGFBR2, ADAM Proteins, Aortic Dissection, 030104 developmental biology, Haploinsufficiency, Fibrillin
Abstract

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 in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants 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 a THSD4 variant and from Thsd4+/− 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.

Published
2021
Full Text
View/download PDF

6. Circulating PCSK9 Linked to Dyslipidemia in Lebanese Schoolchildren

Author

Yara Azar, Marie-Hélène Gannagé-Yared, Elie Naous, Carine Ayoub, Yara Abou Khalil, Elise Chahine, Sandy Elbitar, Youmna Ghaleb, Catherine Boileau, Mathilde Varret, Petra El Khoury, and Marianne Abifadel

Subjects
Endocrinology, Diabetes and Metabolism, lipids (amino acids, peptides, and proteins), pediatric, dyslipidemia, PCSK9, lipoprotein (a), cholesterol, Lebanon, Molecular Biology, Biochemistry
Abstract

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 < 0.0001) but not with TG, HDL-C, and Lp(a). PCSK9 levels were also significantly higher in children with high TC, LDL-C, and non-HDL-C (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.

Published
2022

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

Author

Joel T. Haas, Jan Albert Kuivenhoven, Justina C. Wolters, Andrzej J. Rzepiela, Mathilde Varret, Ann Verhaegen, Valérie Carreau, Szymon Stoma, Anne Philippi, Alaa Othman, Jerome Robert, N. Dalila, Belle V. van Rosmalen, An Verrijken, Arnold von Eckardstein, Bart van de Sluis, Silvija Radosavljevic, Paolo Zanoni, Simon F. Norrelykke, Roger Meier, M. Yalcinkaya, Bart Staels, Andreas Geier, Lucia Rohrer, Michael Stebler, Michele Visentin, Antoine Rimbert, Catherine Boileau, Antonio Gallo, Melinde Wijers, Nicolette C. A. Huijkman, Steve E. Humphries, Jonas Weyler, Freerk van Dijk, Michaela Keel, Srividya Velagapudi, Jean-Pierre Rabès, Marieke Smit, Anne Tybjærg-Hansen, Adriaan van der Graaf, Luisa Vonghia, Yara Abou-Khalil, Sven Francque, Grigorios Panteloglou, Marta Futema, Luc Van Gaal, University hospital of Zurich [Zurich], Universität Zürich [Zürich] = University of Zurich (UZH), Institute for Molecular Systems Biology [ETH Zurich] (IMSB), Department of Biology [ETH Zürich] (D-BIOL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Scientific Center for Optical and Electron Microscopy (ScopeM), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of Groningen [Groningen], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), St George's, University of London, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Saint-Joseph de Beyrouth (USJ), University of Copenhagen = Københavns Universitet (UCPH), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP. Université Paris Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), University of Amsterdam [Amsterdam] (UvA), Columbia University [New York], University Hospital of Würzburg, University College of London [London] (UCL), 603091, ANR-10-LABX-46, 2015T068, CVON2017-2020, AOM06024, 2014/267, Pfizer: 24052829, European Molecular Biology Organization, EMBO: ALTF277-2014, Seventh Framework Programme, FP7, Sixth Framework Programme, FP6: LSHM-CT-2005-018734, Fondation Maladies Rares, FMR, International Atherosclerosis Society, IAS, British Heart Foundation, BHF, European Commission, EC, European Research Council, ERC: 694717, ANR 16-RHUS-0006, Agence Nationale de la Recherche, ANR: ANR-16-RHUS-0007, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF: 310030-185109, 31003A-160126, Fonds De La Recherche Scientifique - FNRS, FNRS, Fonds Wetenschappelijk Onderzoek, FWO: 1802154 N, PG008/08, RG3008, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, NWO: 184.021.007, Universität Zürich, UZH: FK-20-037, We acknowledge the use of data from BIOS-consortium ( http://wiki.bbmri.nl/wiki/BIOS_bios ) which is funded by BBMRI-NL (NWO project 184.021.007). Flow cytometry was performed with equipment of the flow cytometry facility, University of Zurich., This work was conducted as part of the TransCard project of the seventh Framework Program (FP7) granted by the European Commission, to J. Albert Kuivenhoven, A. Tybjaerg-Hansen, and A. von Eckardstein (number 603091) as well as partially the FP7 RESOLVE project (to J.T. Haas, B. Staels, A. Verhaegen, S. Francque, L. Van Gaal, and A. von Eckardstein) and the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46 to B. Staels). Additional work by A. von Eckardstein’s team was funded by the Swiss National Science Foundation (31003A-160126, 310030-185109) and the Swiss Systems X program (2014/267 [Medical Research and Development (MRD)] HDL-X). P. Zanoni received funding awards from the Swiss Atherosclerosis Society (Arbeitsgruppe Lipide und Atherosklerose [AGLA] and the DACH Society for Prevention of Cardiovascular Diseases). G. Panteloglou received funding from the University of Zurich (Forschungskredit, grant no. FK-20-037). J. Albert Kuivenhoven is an Established Investigator from the Dutch Heart Foundation (2015T068). J. Albert Kuivenhoven was also supported by GeniusII (CVON2017-2020). The Laboratory for Vascular Translational Science (L.V.T.S.) team is supported by Fondation Maladies Rares, Programme Hospitalier de Recherche Clinique (PHRC) (AOM06024), and the national project CHOPIN (CHolesterol Personalized Innovation), granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007). Y. Abou Khalil is supported by a grant from Ministère de l’Education Nationale et de la Technologie (France). J.T. Haas was supported by an EMBO Long Term Fellowship (ALTF277-2014). B. Staels is a recipient of an ERC Advanced Grant (no. 694717). Both are also supported by PreciNASH (ANR 16-RHUS-0006). Research at the Antwerp University Hospital was supported by the European Union: FP6 (HEPADIP Contract LSHM-CT-2005-018734). S. Francque has a senior clinical research fellowship from the Fund for Scientific Research (FWO) Flanders (1802154 N). S.E. Humphries received grants RG3008 and PG008/08 from the British Heart Foundation, and the support of the UCLH NIHR BRC. S.E. Humphries directs the UK Children’s FH Register which has been supported by a grant from Pfizer (24052829) given by the International Atherosclerosis Society., This work was conducted as part of the TransCard project of the seventh Framework Program (FP7) granted by the European Commission, to J. Albert Kuivenhoven, A. Tybjaerg-Hansen, and A. von Eckardstein (number 603091) as well as partially the FP7 RESOLVE project (to J.T. Haas, B. Staels, A. Verhaegen, S. Francque, L. Van Gaal, and A. von Eckardstein) and the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46 to B. Staels). Additional work by A. von Eckardstein's team was funded by the Swiss National Science Foundation (31003A-160126, 310030-185109) and the Swiss Systems X program (2014/267 [Medical Research and Development (MRD)] HDL-X). P. Zanoni received funding awards from the Swiss Atherosclerosis Society (Arbeitsgruppe Lipide und Atherosklerose [AGLA] and the DACH Society for Prevention of Cardiovascular Diseases). G. Panteloglou received funding from the University of Zurich (Forschungskredit, grant no. FK-20-037). J. Albert Kuivenhoven is an Established Investigator from the Dutch Heart Foundation (2015T068). J. Albert Kuivenhoven was also supported by GeniusII (CVON2017-2020). The Laboratory for Vascular Translational Science (L.V.T.S.) team is supported by Fondation Maladies Rares, Programme Hospitalier de Recherche Clinique (PHRC) (AOM06024), and the national project CHOPIN (CHolesterol Personalized Innovation), granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007). Y. Abou Khalil is supported by a grant from Minist?re de l'Education Nationale et de la Technologie (France). J.T. Haas was supported by an EMBO Long Term Fellowship (ALTF277-2014). B. Staels is a recipient of an ERC Advanced Grant (no. 694717). Both are also supported by PreciNASH (ANR 16-RHUS-0006). Research at the Antwerp University Hospital was supported by the European Union: FP6 (HEPADIP Contract LSHMCT- 2005-018734). S. Francque has a senior clinical research fellowship from the Fund for Scientific Research (FWO) Flanders (1802154 N). S.E. Humphries received grants RG3008 and PG008/08 from the British Heart Foundation, and the support of the UCLH NIHR BRC. S.E. Humphries directs the UK Children's FH Register which has been supported by a grant from Pfizer (24052829) given by the International Atherosclerosis Society., ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Center for Liver, Digestive and Metabolic Diseases (CLDM), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), HAL UVSQ, Équipe, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Spliceosome, Physiology, RNA Splicing, Population, Hypercholesterolemia, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Gene expression, medicine, Humans, education, Gene, 030304 developmental biology, 0303 health sciences, Gene knockdown, education.field_of_study, Intron, Nuclear Proteins, Hep G2 Cells, medicine.disease, Molecular biology, Endocytosis, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Lipoproteins, LDL, Cholesterol, HEK293 Cells, Cardiovascular diseases, Liver, Receptors, LDL, Mutation, LDL receptor, Hepatocytes, Spliceosomes, lipids (amino acids, peptides, and proteins), Human medicine, Cardiology and Cardiovascular Medicine
Abstract

Background: The LDLR (low-density lipoprotein receptor) 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 data sets 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 nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25 , are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25 , overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. Conclusions: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.

Published
2022
Full Text
View/download PDF

8. APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

Author

Yara Abou Khalil, Oriane Marmontel, Jean Ferrières, François Paillard, Cécile Yelnik, Valérie Carreau, Sybil Charrière, Eric Bruckert, Antonio Gallo, Philippe Giral, Anne Philippi, Olivier Bluteau, Catherine Boileau, Marianne Abifadel, Mathilde Di-Filippo, Alain Carrié, Jean-Pierre Rabès, Mathilde Varret, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Pontchaillou [Rennes], Centre de référence des maladies auto-immunes systémiques rares du Nord et Nord Ouest [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Sorbonne Université - Faculté de médecine [CHU Pitié Salpétrière], CIC Hôpital Bichat, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Agence Nationale de la Recherche, ANR: ANR-16-RHUS-0007, Institut National de la Santé et de la Recherche Médicale, Inserm, Conseil National de la Recherche Scientifique, CNRS, This work was supported by grants from the national project CHOPIN (CHolesterol Person-alized Innovation) granted by the National Research Agency (ANR-16-RHUS-0007), INSERM (Institut National de la Santé et de la Recherche Médicale). YAK was supported by a grant from Ministère de l’Education Nationale et de la Technologie (France), a grant from Nouvelle Société Francophone de l’Athérosclérose (France), and grants from the Lebanese National Council for Scientific Research (CNRS-L) and the Council of Research of Saint-Joseph University of Beirut, Lebanon., and HAL UVSQ, Équipe

Subjects
hypercholesterolemia, ADH, FCHL, apolipoprotein E, APOE gene, mutation, variant, [SDV]Life Sciences [q-bio], Organic Chemistry, nutritional and metabolic diseases, General Medicine, Catalysis, Computer Science Applications, Inorganic Chemistry, [SDV] Life Sciences [q-bio], lipids (amino acids, peptides, and proteins), Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

International audience; Primary 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.

Published
2022
Full Text
View/download PDF

9. APOE gene variants in primary dyslipidemia

Author

Mathilde Varret, Jean-Pierre Rabès, Catherine Boileau, Yara Abou Khalil, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Université Paris Cité (UPCité), Université Saint-Joseph de Beyrouth (USJ), Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 13CVD03 Agence Nationale de la Recherche, ANR: ANR-16-RHUS-0007 Fondation Leducq Institut National de la Santé et de la Recherche Médicale, Inserm Conseil National de la Recherche Scientifique, CNRS-L, YAK is supported by a grant from Ministère de l’Education Nationale et de la Technologie (France) , a grant from Nouvelle Société Francophone de l’Athérosclérose (France) , and a grant from Lebanese National Council for Scientifc Research (CNRS-L) ., This work was supported by grants from Leducq Foundation (FLQ # 13CVD03), The national project CHOPIN (CHolesterol Personalized Innovation) granted by the National Research Agency (ANR-16-RHUS-0007), INSERM (Institut National de la Sant? et de la Recherche M?dicale), Conseil de la recherche of Saint-Joseph University of Beirut, and CEDRE program.YAK is supported by a grant from Minist?re de l'Education Nationale et de la Technologie (France), a grant from Nouvelle Soci?t? Francophone de l'Ath?roscl?rose (France), and a grant from Lebanese National Council for Scientifc Research (CNRS-L)., This work was supported by grants from Leducq Foundation ( FLQ # 13CVD03 ), The national project CHOPIN (CHolesterol Personalized Innovation) granted by the National Research Agency ( ANR-16-RHUS-0007 ), INSERM (Institut National de la Santé et de la Recherche Médicale) , Conseil de la recherche of Saint-Joseph University of Beirut , and CEDRE program ., ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), HAL UVSQ, Équipe, CHOPIN - - CHOPIN2016 - ANR-16-RHUS-0007 - RHUS - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, and Université de Paris (UP)

Subjects
0301 basic medicine, Apolipoprotein E, Candidate gene, Genetic variants, Apolipoprotein B, Familial dysbetalipoproteinemia, Familial combined hyperlipidemia, [SDV]Life Sciences [q-bio], Familial hypercholesterolemia, Hypercholesterolemia, Lipoprotein glomerulopathy, 030204 cardiovascular system & hematology, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, Apolipoproteins E, medicine, Humans, Dyslipidemias, Genetics, biology, PCSK9, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Autosomal dominant, Receptors, LDL, LDL receptor, biology.protein, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Dysbetalipoproteinemia, Cardiology and Cardiovascular Medicine, APOE, Lipoprotein
Abstract

International audience; Apolipoprotein 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.

Published
2021
Full Text
View/download PDF

10. Plasma proprotein-convertase-subtilisin/kexin type 9 (PCSK9) and cardiovascular events in type 2 diabetes

Author

Louis Potier, Francesco Andreata, Sandy Elbitar, Catherine Boileau, Boris Hansel, Mathilde Varret, Samy Hadjadj, Yara Abou-Khalil, Michel Marre, Ronan Roussel, Petra El Khoury, Marianne Abifadel, Gilberto Velho, Kamel Mohammedi, Marie-Paule Jacob, Frédéric Fumeron, Philippe Gabriel Steg, Giusepinna Caligiuri, Stéphanie Ragot, Youmna Ghaleb, El Khoury, P, Roussel, R, Fumeron, F, Abou-Khalil, Y, Velho, G, Mohammedi, K, Jacob, M, Steg, P, Potier, L, Ghaleb, Y, Elbitar, S, Ragot, S, Andreata, F, Caligiuri, G, Hadjadj, S, Boileau, C, Marre, M, Abifadel, M, Varret, M, and Hansel, B

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, dyslipidaemia, Endocrinology, Diabetes and Metabolism, Myocardial Infarction, Type 2 diabetes, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Risk Factors, cardiovascular disease, Internal medicine, cohort study, Internal Medicine, medicine, Humans, Myocardial infarction, Stroke, Aged, business.industry, Incidence, Incidence (epidemiology), PCSK9, MED/04 - PATOLOGIA GENERALE, Hazard ratio, Type 2 Diabetes Mellitus, Middle Aged, medicine.disease, Confidence interval, 030104 developmental biology, Diabetes Mellitus, Type 2, type 2, Cardiovascular Diseases, Cardiology, Female, Proprotein Convertase 9, business, Biomarkers, Diabetic Angiopathies, Follow-Up Studies
Abstract

Aim: To investigate whether plasma concentrations of proprotein-convertase-subtilisin/kexin type 9 (PCSK9) were associated with cardiovascular (CV) events in two cohorts of patients with type 2 diabetes mellitus. Methods: We considered patients from the DIABHYCAR (n = 3137) and the SURDIAGENE (n = 1468) studies. Baseline plasma PCSK9 concentration was measured using an immunofluorescence assay. In post hoc, but preplanned, analyses we assessed the relationship between PCSK9 and the following endpoints: (1) a combined endpoint of major CV events: CV death, non-fatal myocardial infarction (MI), stroke and heart failure-related hospital admission; (2) a composite of all CV events: MI, stroke, heart failure-related hospital admission, coronary/peripheral angioplasty or bypass, CV death; (3) MI; (4) stroke/transient ischaemic attack (TIA); and (5) CV death. Results: In the DIABHYCAR study, plasma PCSK9 tertiles were associated with the incidence of MI, all CV events and stroke/TIA (P for trend

Published
2018
Full Text
View/download PDF

11. PCSK9 in the development of human atherosclerosis

Author

C. Le Goff, Mathilde Varret, Youmna Ghaleb, Yara Azar, Catherine Deschildre, Isabelle Guillas, Catherine Boileau, M.-N. Lebel, M. Abi Fadel, Michel Jb, Yara Abou-Khalil, P. El Khoury, W. Le Goff, Sebastien Dupont, and Sandy Elbitar

Subjects
business.industry, PCSK9, Medicine, Cardiology and Cardiovascular Medicine, business, Bioinformatics
Published
2021
Full Text
View/download PDF

12. Identification of the first Tangier disease patient in Lebanon carrying a new pathogenic variant in ABCA1

Author

Petra El Khoury, Carine Ayoub, Philippe Giral, Catherine Boileau, Maryse Guerin, Yara Abou-Khalil, Mathilde Varret, Alexandre Superville, Jean-Pierre Rabès, Marianne Abifadel, Selim Jambart, Sandy Elbitar, Yara Azar, Alain Carrié, Wilfried Le Goff, Youmna Ghaleb, and Philippe Couvert

Subjects
0301 basic medicine, Proband, Adult, Male, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, Population, Consanguinity, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Tangier disease, Internal Medicine, medicine, Humans, Lebanon, education, Hypoalphalipoproteinemia, Tangier Disease, Aged, Aged, 80 and over, education.field_of_study, Nutrition and Dietetics, biology, business.industry, Cholesterol, HDL, Genetic Variation, Exons, Middle Aged, medicine.disease, Pedigree, 030104 developmental biology, ABCA1, Immunology, biology.protein, lipids (amino acids, peptides, and proteins), Female, Cardiology and Cardiovascular Medicine, business, Dyslipidemia, ATP Binding Cassette Transporter 1
Abstract

Background The Middle East region is characterized by low levels of high-density lipoprotein cholesterol (HDL-C). To date, no genetic study has investigated the cause of low HDL-C in the Lebanese population. Objective Our objective was to study the genetic causes for hypoalphalipoproteinemia in a Lebanese family with extremely low HDL-C levels. Methods We sequenced the ABCA1 gene and evaluated cholesterol efflux, inflammatory, and metabolic profiles in the proband and his family. Results We identified the first Lebanese pathogenic variant in ABCA1 gene causing Tangier disease in a consanguineous family. The proband carried a novel homozygous pathogenic variant p.Gly592Asp in exon 14 of ABCA1, which segregated with the disease in the family. Functional study of the p.Gly592Asp pathogenic variant revealed that lipid-free apolipoprotein A-I–dependent cholesterol efflux was completely abolished in cholesterol-loaded human monocytes-derived macrophages isolated from the proband when compared to controls. Systemic inflammatory and metabolic assessments showed that plasma cytokines (MCP-1, MIP-1α, IL-6, CRP, TNF-α), adhesion molecules (ICAM-1, VCAM-1, E-selectin), inflammatory soluble receptors (sIL-6r, sTNFRI, sTNFRII), and metabolic markers (Insulin, C-peptide) were elevated in the proband when compared to controls. Noninvasive cardiovascular investigation revealed the presence of premature artery lesions in the proband. Conclusions It is the first case of Tangier disease reported in Lebanon harboring a novel pathogenic variant in ABCA1. Further genetic research is needed in the Middle East where the consanguinity rate is elevated, to understand the cause of the highly prevalent dyslipidemia. This will help guiding the early diagnosis, management, and prevention of cardiovascular complications.

Published
2018

13. PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies

Author

Youmna Ghaleb, Yara Abou Khalil, Petra El Khoury, Mathilde Varret, Catherine Boileau, Sandy Elbitar, and Marianne Abifadel

Subjects
Oncology, medicine.medical_specialty, Hypercholesterolemia, Translational research, Familial hypercholesterolemia, Disease, 030204 cardiovascular system & hematology, Hyperlipoproteinemia Type II, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Medicine, Humans, 030212 general & internal medicine, Alirocumab, Clinical Trials as Topic, business.industry, Cholesterol, PCSK9, Anticholesteremic Agents, PCSK9 Inhibitors, Antibodies, Monoclonal, medicine.disease, Clinical trial, Evolocumab, Endocrinology, chemistry, Mutation, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business
Abstract

In 2003, Abifadel et al. (Nat. Genet. 34:154–156, 2003) identified PCSK9, encoding proprotein convertase subtilisin/kexin type 9, as the third causal gene for autosomal dominant hypercholesterolemia. This review focuses on the main steps from this major breakthrough in familial hypercholesterolemia (FH) to the latest clinical trials with the anti-PCSK9 antibodies. The year 2015 was remarkable in cardiovascular disease through the field of cholesterol. Nearly 30 years after the discovery of statins, a new class of effective lipid-lowering drugs has emerged: the anti-PCSK9 antibodies. The discovery of the first gain-of-function mutations of PCSK9 in FH rapidly became the center of interest of researchers worldwide. Preclinical and clinical studies launched by pharmaceutical companies led to the first three anti-PCSK9 antibodies, two of which (evolocumab and alirocumab) reduce LDL cholesterol levels by 50–60% and received FDA and European Medicines Agency approvals in 2015 on top of statin therapy. Recently, results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, the outcome trial of evolocumab over 2.2 years, showed a reduction of 15–20% in the risk of major cardiovascular outcomes in high-risk patients receiving statin therapy. Results of ODYSSEY OUTCOMES trial, evaluating the effect of alirocumab in 18,000 patients with established CVD are also eagerly awaited in 2018. The evolution of research on PCSK9, starting from the discovery of the first set of mutations in PCSK9 in FH in 2003, is an amazing example of successful translational research. It shows how rigorous and powered genetic analyses can lead to the discovery of a new class of lipid-lowering drugs that give hope in fighting high cholesterol levels and their cardiovascular complications.

Published
2017

Catalog

Books, media, physical & digital resources
See catalog results