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1. 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
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2. 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
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3. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia

Author: Mathilde Di Filippo, Hervé Créhalet, Marie Elisabeth Samson-Bouma, Véronique Bonnet, Lawrence P. Aggerbeck, Jean-Pierre Rabès, Frederic Gottrand, Gérald Luc, Dominique Bozon, and Agnès Sassolas
Subjects: dyslipidemias, familial hypocholesterolemia, chylomicrons, lipoprotein/assembly, hepatosteatosis, genetics, Biochemistry, QD415-436
Abstract: Abetalipoproteinemia (ABL) is an inherited disease characterized by the defective assembly and secretion of apolipoprotein B–containing lipoproteins caused by mutations in the microsomal triglyceride transfer protein large subunit (MTP) gene (MTTP). We report here a female patient with an unusual clinical and biochemical ABL phenotype. She presented with severe liver injury, low levels of LDL-cholesterol, and subnormal levels of vitamin E, but only mild fat malabsorption and no retinitis pigmentosa or acanthocytosis. Our objective was to search for MTTP mutations and to determine the relationship between the genotype and this particular phenotype. The subject exhibited compound heterozygosity for two novel MTTP mutations: one missense mutation (p.Leu435His) and an intronic deletion (c.619-5_619-2del). COS-1 cells expressing the missense mutant protein exhibited negligible levels of MTP activity. In contrast, the minigene splicing reporter assay showed an incomplete splicing defect of the intronic deletion, with 26% of the normal splicing being maintained in the transfected HeLa cells. The small amount of MTP activity resulting from the residual normal splicing in the patient explains the atypical phenotype observed. Our investigation provides an example of a functional analysis of unclassified variations, which is an absolute necessity for the molecular diagnosis of atypical ABL cases.
Published: 2012
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4. Effect of causative genetic variants on atherosclerotic cardiovascular disease in heterozygous familial hypercholesterolemia patients

Author: Anthony Matta, Jean Pierre Rabès, Dorota Taraszkiewicz, Didier Carrié, Jérôme Roncalli, and Jean Ferrières
Subjects: heterozygous familial hypercholesterolemia, genetic variant, cardiovascular disease, LDL-c, atherosclerosis, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: BackgroundHeterozygous familial hypercholesterolemia (HFH) is an autosomal dominant genetic disorder leading to a lifetime exposure to high low-density lipoprotein cholesterol (LDL-c) level and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We evaluate the effect of a causative genetic variant to predict ASCVD in HFH patients undergoing treatment.Materials and methodsA retrospective cohort was conducted on 289 patients with possible, probable, and definite diagnosis of HFH according to Dutch Lipid Clinic Network Score and in whom DNA analyses were performed and mean LDL-c level was above 155 mg/dl. The study population was divided into groups based on the presence or not of a causative variant (pathogenic or likely pathogenic). We observed each of the study’s participants for the occurrence of ASCVD.ResultsA causative variant was detected in 42.2% of study participants, and ASCVD has occurred in 21.5% of HFH patients. The incidence of ASCVD (27% vs. 17.4%, p = 0.048) and the mean of LDL-c under an optimal medical treatment (226 ± 59 mg/dl vs. 203 ± 37 mg/dl, p = 0.001) were higher in HFH-causative variant carriers than others. After adjusting on confounders, ASCVD was positively associated with LDL-c level [OR = 2.347; 95% (1.305–4.221), p = 0.004] and tends toward a negative association with HDL-c level [OR = 0.140; 95% (0.017–1.166), p = 0.059]. There is no more association between the detection of a causative variant and the occurrence of ASCVD [OR = 1.708; 95% (0.899–3.242), p = 0.102]. Kaplan Meier and log rank test showed no significant differences in event-free survival analysis between study groups (p = 0.523).ConclusionIn this study population under medical care, it seems that the presence of a causative variant did not represent an independent predictor of adverse cardiovascular outcomes in HFH patients, and LDL-c level played an undisputable causal role.
Published: 2023
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5. 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
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6. Featured Cover

Author: Dominique P. Germain, Thierry Levade, Eric Hachulla, Bertrand Knebelmann, Didier Lacombe, Vanessa Leguy Seguin, Karine Nguyen, Esther Noël, and Jean‐Pierre Rabès
Subjects: Genetics, Genetics (clinical)
Published: 2022
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7. Prevalence of familial hypercholesterolaemia in patients presenting with premature acute coronary syndrome

Author: Marie, Hauguel-Moreau, Vincent, Aïdan, Hélène, Hergault, Alain, Beauchet, Marion, Pépin, Giulio, Prati, Rémy, Pillière, Mounir, Ouadahi, Loïc, Josseran, Christophe, Rodon, Jean-Pierre, Rabès, Philippe, Charron, Olivier, Dubourg, Ziad, Massy, Nicolas, Mansencal, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Caisse primaire d'assurance maladie (CPAM), Université Paris-Saclay, 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), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Garnier, Sophie
Subjects: Epidemiology, Dutch Lipid Clinic Network score, [SDV]Life Sciences [q-bio], Score de Dutch, General Medicine, Acute myocardial infarction, Middle Aged, Hyperlipoproteinemia Type II, [SDV] Life Sciences [q-bio], Risk Factors, Prevalence, Humans, Prospective Studies, Acute Coronary Syndrome, Cardiology and Cardiovascular Medicine, Familial hypercholesterolaemia
Abstract: International audience; ackground: Familial hypercholesterolaemia (FH) is responsible for severe hypercholesterolaemia and premature cardiovascular morbidity and mortality. The first clinical event is typically an acute coronary syndrome. Unfortunately, FH is largely underdiagnosed in the general population.Aims: To assess the prevalence of clinical FH among patients with premature (aged≤50 years) acute myocardial infarction (MI) and compare it with FH prevalence in a control population.Methods: We reviewed in our database all patients with premature MI (aged≤50 years) referred to Ambroise Paré Hospital from 2014 to 2018. FH prevalence was estimated via the Dutch Lipid Clinic Network score, based on personal and family history of premature cardiovascular disease and low-density lipoprotein cholesterol concentrations. FH was "possible" with a score between 3 and 5 points, "probable" with a score between 6 and 8 and "definite" with a score above 8. FH prevalence in young patients with MI was then compared with FH prevalence in a general population of the same age from the CARVAR 92 prospective cohort.Results: Of the 457 patients with premature MI, 29 (6%) had "probable" or "definite" FH. In the CARVAR 92 cohort, 16 (0.16%) of 9900 subjects aged≤50 years had "probable" or "definite" FH. FH prevalence was 39 times greater among patients with premature MI than in the control population (P30-fold more common in patients referred for premature MI than in the general population; this highlights the need for FH screening after a first MI to enhance lipid-lowering therapy and allow early identification of family members.
Published: 2022
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8. 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
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9. 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
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10. Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease

Author: Dominique P. Germain, Thierry Levade, Eric Hachulla, Bertrand Knebelmann, Didier Lacombe, Vanessa Leguy Seguin, Karine Nguyen, Esther Noël, Jean‐Pierre Rabès, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), AP-HP. Université Paris Saclay, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Claude Huriez [Lille], CHU Lille, Faculté de Médecine Henri Warembourg - Université de Lille, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Strasbourg, Takeda Pharmaceutical Company, TPC, Sanofi Genzyme, D.P.G.: Consultant for Sanofi‐Genzyme, Idorsia, Takeda, speaker's honoraria from Takeda, Amicus, Sanofi‐Genzyme. T.L.: Hotel/travel grants from Sanofi‐Genzyme, Takeda, BioMarin, Enzyvant, Orphan. E.H.: Speaker's honoraria and/or travel grants from Sanofi‐ Genzyme, GSK, Actelion, Sobi, B.K.: Speaker's honoraria from Travere, Sanofi, Alnylam, Reata, hotel/travel grants from Sanofi, Travere, Reata, D.L.: Speaker's honoraria and hotel/travel expenses from Amicus, Sanofi‐Genzyme. V.L.S.: Speaker's honoraria from Sanofi‐Genzyme, hotel/travel grants from Amicus, Orphan, Takeda, Sanofi‐Genzyme, K.N.: Speaker's honoraria, travel grants from Sanofi Genzyme, grants from Amicus therapeutics, E.N.: Speaker's honoraria and/or travel grants from Amicus Therapeutics, Sanofi‐Genzyme. J.P.R.: Consultant for Sanofi‐Genzyme, hotel/travel expenses from Amicus Therapeutics, speaker's honoraria from Amgen., and The authors received editorial/writing support in the preparation of this manuscript that was founded by Sanofi Genzyme, but no payment for writing this publication. The authors are responsible for the content of this manuscript and the decision to submit the manuscript for publication.
Subjects: Fabry disease, genetic variants, [SDV]Life Sciences [q-bio], experts, ACMG criteria, Phenotype, Gene Frequency, alpha-Galactosidase, Mutation, Genetics, Humans, Female, pathogenicity interpretation, Genetics (clinical), variants of unknown significance
Abstract: International audience; Fabry disease (FD) is an X-linked genetic disease due to pathogenic variants in GLA. The phenotype varies depending on the GLA variant, alpha-galactosidase residual activity, patient's age and gender and, for females, X chromosome inactivation. Over 1000 variants have been identified, many through screening protocols more susceptible to disclose non-pathogenic variants or variants of unknown significance (VUS). This, together with the non-specificity of some FD symptoms, challenges physicians attempting to interpret GLA variants. The traditional way to interpreting pathogenicity is based on a combined approach using allele frequencies, genomic databases, global and disease-specific clinical databases, and in silico tools proposed by the American College of Medical Genetics and Genomics. Here, a panel of FD specialists convened to study how expertise may compare with the traditional approach. Several GLA VUS, highly controversial in the literature (p.Ser126Gly, p.Ala143Thr, p.Asp313Tyr), were re-analyzed through reviews of patients' charts. The same was done for pathogenic GLA variants with some specificities. Our data suggest that input of geneticists and physicians with wide expertise in disease phenotypes, prevalence, inheritance, biomarkers, alleles frequencies, disease-specific databases, and literature greatly contribute to a more accurate interpretation of the pathogenicity of variants, bringing a significant additional value over the traditional approach.
Published: 2022
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11. LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Author: Mathilde Varret, Jean-Pierre Rabès, Rochelle Thiart, Maritha J. Kotze, Heike Baron, Ana Cenarro, Olivier Descamps, Margit Ebhardt, Jean-Claude Hondelijn, Gert M. Kostner, Yasuko Miyake, Miguel Pocovi, Hartmut Schmidt, Helena Schmidt, Herbert Schuster, Manfred Stuhrmann, Taku Yamamura, Claudine Junien, Christophe Béroud, and Catherine Boileau
Published: 1998
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12. Software and database for the analysis of mutations in the human LDL receptor gene.

Author: Mathilde Varret, Jean-Pierre Rabès, Gwenaëlle Collod-Béroud, Claudine Junien, Catherine Boileau, and Christophe Béroud
Published: 1997
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13. Real-World Efficacy of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (PCSK9i) in Heterozygous Familial Hypercholesterolemia Patients Referred for Lipoprotein Apheresis

Author: Anthony Matta, Dorota Taraszkiewicz, Vanina Bongard, Jean Ferrières, Frédéric Bouisset, and Jean-Pierre Rabès
Subjects: Male, medicine.medical_specialty, Statin, medicine.drug_class, Lipoproteins, Population, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Gastroenterology, Cohort Studies, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, Ezetimibe, Clinical Research, Internal medicine, medicine, Humans, Subtilisins, education, Hypolipidemic Agents, Dyslipidemias, education.field_of_study, business.industry, PCSK9 Inhibitors, Subtilisin, Cholesterol, LDL, General Medicine, Middle Aged, Lipid Metabolism, medicine.disease, Proprotein convertase, Lipids, 030220 oncology & carcinogenesis, Blood Component Removal, Kexin, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Lipoprotein apheresis, medicine.drug
Abstract: BACKGROUND A small proportion of familial hypercholesterolemia (FH) patients can adequately control this condition, although achieving the recommended targets for low-density lipoprotein cholesterol (LDL-c) levels remains a challenge. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are new and potent lipid-lowering drugs. However, there is scarce literature on real-world data about their use in patients with FH. MATERIAL AND METHODS We examined the reduction in LDL-c levels from the baseline, after PCSK9i initiation in heterozygous familial hypercholesterolemia patients referred for lipoprotein apheresis in our regional lipid clinic. The study was conducted from March 2018 to September 2019, the period immediately after PCSK9i reimbursement was available in France. PCSK9i was added on top of the patients' maximal tolerated lipid-lowering regimens. RESULTS The study had 123 patients with heterozygous FH. The mean age of the patients was 59±11 years. The mean baseline LDL-c for all the participants was 277±78 mg/dl. It was 283±81 mg/dl in the PCSK9i monotherapy group (n=83), 247±68 mg/dl in the PCSK9i plus ezetimibe group (n=12), and 264±78 mg/dl in the PCSK9i plus statin and ezetimibe group (n=28). The mean decrease observed in the LDL-c level from baseline was 136±70 mg/dl (n=123), 125±60 mg/dl (n=83), 103±77 mg/dl (n=12), and 175±70 mg/dl (n=28), respectively. CONCLUSIONS An overall reduction of 49.1% from the baseline LDL-c was observed in the heterozygous FH population after PCSK9i initiation in a real-world experience. The group treated with PCSK9i ezetimibe plus statin showed further reduction of their LDL-c levels with a better responder rate, achieving the target 50% reduction in LDL-c from the baseline.
Published: 2021
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14. 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
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15. Évaluation par RT-PCR du portage nasopharyngé du SARS-Cov-2 chez les personnels de santé symptomatiques suspects de COVID-19 dans un CHU de la banlieue parisienne

Author: S. Greffe, A. Van der Heidjen, G. Do Rosario, J. Tysebaert, E. Rouveix, A. Huet, Jean-Pierre Rabès, C. Babulle, Q. Vauvillier, F. Espinasse, M.C. Gramer, B. Mantalvan, C. Duran, Thierry Chinet, L.F. Kramarz, F. Moreau, G. Pellissier, S. Labrune, M. Sirol, Service d'ophtalmologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Service de pneumologie, Service de radiologie, CHU Toulouse [Toulouse], Service de rhumatologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Biochimie et Génétique Moléculaire, Hôpital Beaujon [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Gynecology, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), biology, business.industry, Carrier state, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], 010102 general mathematics, Nasopharyngeal carriage, Gastroenterology, biology.organism_classification, University hospital, 01 natural sciences, 3. Good health, 03 medical and health sciences, Health personnel, 0302 clinical medicine, Internal Medicine, Medicine, 030212 general & internal medicine, 0101 mathematics, business, Betacoronavirus
Abstract: Resume Introduction Une consultation dediee aux professionnels de sante symptomatiques a ete ouverte au debut de l'epidemie de COVID-19, afin de repondre aux besoins specifiques de cette population. L'objectif de ce travail etait d'estimer la frequence du portage nasopharynge du SARS-Cov-2 chez les personnels de sante symptomatiques suspects de COVID-19, et de determiner les facteurs associes a ce portage. Methodes Etude descriptive des caracteristiques cliniques et epidemiologiques des consultants, conduite du 5 mars au 17 avril 2020. Le recueil des donnees cliniques et des resultats du test RT-PCR a ete conduit a l'aide de formulaires standardises. Resultats Des 522 consultants, 308 exercaient a l'Hopital et 214 a l'exterieur. Ils avaient des formes benignes de COVID-19 et des signes cliniques non specifiques a l'exception de l'agueusie/anosmie, significativement plus frequente chez ceux avec RT-PCR positive. Le taux de positivite de la RT-PCR etait globalement de 38 %, sans difference significative selon la profession, superieur chez les consultants exterieurs (47 % versus 31 %). A l'hopital, ce taux etait significativement moindre pour les personnels symptomatiques des secteurs de soins, compare aux personnels des plateaux techniques et laboratoires (24 %, versus 45 %, p = 0,006 et 54 %, p Conclusions Ces donnees confirment l'impact fort du COVID-19 sur les professionnels de sante. Les taux de positivite plus eleves chez les professionnels symptomatiques exercant en dehors de l'hopital, comparativement a ceux exercant a l'hopital, pourraient s'expliquer en partie par une penurie en equipements de protection et par des difficultes d'acces au diagnostic virologique, qui etaient plus importants en dehors de l'hopital quand l'epidemie a commence.
Published: 2020
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16. Hypercholestérolémie familiale peu diagnostiquée, insuffisamment traitée. Enquête auprès de 495 médecins

Author: Jean Ferrières, Eric Bruckert, Bertrand Cariou, Nicolas Danchin, Jean-Pierre Rabès, Michel Krempf, Michel Farnier, and Sophie Béliard
Subjects: Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, business.industry, Medicine, 030212 general & internal medicine, General Medicine, 030204 cardiovascular system & hematology, business, 3. Good health
Abstract: Resume Introduction L’hypercholesterolemie familiale heterozygote (HF) est l’une des maladies genetiques les plus frequentes avec une incidence de l’ordre de 1/250. Elle est caracterisee par un taux de cholesterol tres eleve depuis la naissance souvent responsable de maladies cardiovasculaires (CV) atteignant des patients jeunes. Alors qu’un diagnostic precoce et une prise en charge therapeutique adaptee permettent d’eviter les complications CV de la maladie, l’HF est largement sous-diagnostiquee et donc sous-traitee. Methodes Afin de faire un etat des lieux de la prise en charge de l’HF en France, nous avons mene une enquete aupres de 495 medecins generalistes (n = 200) et specialistes (n = 295) susceptibles de suivre ces patients. Resultats Les resultats ont revele une large sous-estimation du risque CV et une forte inertie therapeutique dans la prise en charge des patients atteints. Les medecins ont fait etat d’un reel besoin d’information sur la maladie. Conclusion Compte tenu de la frequence de l’HF et du poids de la morbi-mortalite cardiovasculaire associee, les medecins generalistes ont un role decisif a jouer dans l’identification et la prise en charge de ces patients. La publication recente de recommandations de la HAS sur les modalites de depistage familial de l’HF devrait permettre une amelioration de la prise en charge de cette maladie.
Published: 2018
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17. Interpreting the pathogenicity of genetic variants in rare diseases: Lessons from Fabry disease

Author: Dominique P. Germain, Thierry Levade, Eric Hachulla, Bertrand Knebelmann, Didier Lacombe, and Jean-Pierre Rabès
Subjects: Endocrinology, Endocrinology, Diabetes and Metabolism, Genetics, Molecular Biology, Biochemistry
Published: 2022
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18. Hypercholestérolémie familiale : un risque cardiovasculaire largement sous-estimé

Author: B. Cariou, Jean Ferrières, M. Farnier, Michel Krempf, Jean-Pierre Rabès, S. Béliard, Nicolas Danchin, and Eric Bruckert
Subjects: Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, business.industry, medicine, 030212 general & internal medicine, Cascade screening, 030204 cardiovascular system & hematology, Cardiology and Cardiovascular Medicine, business, 3. Good health
Abstract: Resume Contexte L’hypercholesterolemie familiale est une dyslipidemie hereditaire monogenique (autosomique dominante) caracterisee par une augmentation permanente et isolee du cholesterol transporte par les lipoproteines de basse densite. La prevalence de sa forme heterozygote est estimee entre 1/500 et 1/250, et en l’absence de traitement specifique, l’hypercholesterolemie familiale heterozygote est responsable d’une augmentation d’un facteur 13 du risque de coronaropathie precoce par rapport aux patients non atteints par la maladie. Objectifs Faire un etat des lieux de la connaissance de l’hypercholesterolemie familiale heterozygote en France aupres des medecins impliques dans la prise en charge de la pathologie. Methodes Au travers de questionnaires soumis par telephone et par Internet, une enquete a ete menee aupres d’un echantillon representatif de 495 medecins (cardiologues, endocrinologues/diabetologues, gynecologues, medecins generalistes) qui, en parallele, ont complete 579 fiches patient. Resultats Trente-deux pour cent (IC 95 % [27,8 ; 36,2]) des medecins declaraient faire la difference entre hypercholesterolemie polygenique et hypercholesterolemie familiale. La presence de xanthomes tendineux, un element cle du diagnostic, etait spontanement citee par 44 % (IC 95 % [34 ; 54,2]) des cardiologues. Six pour cent (IC 95 % [2,2 ; 12,6]) d’entre eux donnaient une estimation correcte de la prevalence de l’hypercholesterolemie familiale. La probabilite de transmission de l’hypercholesterolemie familiale heterozygote, quand un des parents est atteint, etait connue pour 59 % (IC 95 % [48,7 ; 68,7]) des cardiologues interroges. Un depistage en cascade etait effectue de facon systematique par 4 % (IC 95 % [1,1 ; 9,9]) d’entre eux. Dix-huit pour cent (IC 95 % [11 ; 26,9]) des cardiologues estimaient le risque cardiovasculaire supplementaire de l’hypercholesterolemie familiale heterozygote superieur a 10. Cinquante-sept pour cent (IC 95 % [46,7 ; 66,8]) des cardiologues admettaient etre mal informes sur l’hypercholesterolemie familiale heterozygote et 83 % (IC 95 % [74,1 ; 89,7]) exprimaient un besoin d’informations sur cette pathologie. Conclusion Le manque de connaissance de l’hypercholesterolemie familiale heterozygote et de son risque cardiovasculaire associe est probablement a l’origine d’un defaut de diagnostic conduisant a une prise en charge inadaptee de cette maladie.
Published: 2018
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19. Usefulness of the genetic risk score to identify phenocopies in families with familial hypercholesterolemia?

Author: Gérald Luc, Harout Iliozer, Sandy Elbitar, Youmna Ghaleb, Valérie Carreau, Catherine Boileau, Eric Bruckert, Marianne Abifadel, Alain Carrié, Michel Farnier, Petra El Khoury, Sybil Charrière, Philippe Moulin, Jean-Pierre Rabès, Mathilde Varret, M. Di-Filippo, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Apolipoprotein E, Multifactorial Inheritance, Biochemistry & Molecular Biology, medicine.medical_specialty, Apolipoprotein B, [SDV]Life Sciences [q-bio], Hypercholesterolemia, prevalence, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, low, autosomal-dominant hypercholesterolemia, 03 medical and health sciences, Apolipoproteins E, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, Genetic Testing, Genetics (clinical), Genetics & Heredity, Phenocopy, pcsk9, biology, business.industry, PCSK9, fungi, mutations, medicine.disease, ldl, 3. Good health, Phenotype, 030104 developmental biology, Endocrinology, Apolipoprotein B-100, LDL receptor, biology.protein, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, atherosclerosis, coronary-heart-disease, business, Lipoprotein
Abstract: International audience; Familial hypercholesterolemia (FH) is caused by mutations in LDLR (low-density lipoprotein receptor), APOB (apolipoprotein B), PCSK9 (proprotein convertase subtilisin/kexin type 9), or APOE (apolipoprotein E) genes in approximately 80% of the cases. Polygenic forms of hypercholesterolemia may be present among patients clinically diagnosed with FH but with no identified mutation (FH mutation-negative (FH/M-)). To address whether polygenic forms may explain phenocopies in FH families, we calculated a 6-single-nucleotide polymorphism (SNP) genetic risk score (GRS) in all members from five French FH families where a mutation was identified (FH/M+) as well as some phenocopies (FH/M-). In two families, three FH/M- patients present a high GRS suggesting a polygenic hypercholesterolemia for these phenocopies. However, a high GRS is also observed in nine FH/M+ patients and in four unaffected relatives from three families. These observations indicate that the GRS does not seem to be a good diagnostic tool at the individual level. Nevertheless, the GRS seems to be a contributor of the severity of hypercholesterolemia since patients who cumulate a mutation and a high GRS exhibit higher low-density lipoprotein cholesterol levels when compared to patients with only FH (p = 0.054) or only polygenic hypercholesterolemia (p = 0.0039). In conclusion, the GRS can be used as a marker of the severity of hypercholesterolemia but does not seem to be a reliable tool to distinguish phenocopies within FH families.
Published: 2018
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20. Proprotein convertase subtilisin / kexin 9 (PCSK9) inhibitors and the future of dyslipidemia therapy: an updated patent review (2011-2015)

Author: Youmna Ghaleb, Petra El Khoury, Mathilde Varret, Catherine Boileau, Jean-Pierre Rabès, Nabil G. Seidah, Marianne Abifadel, and Sandy Elbitar
Subjects: 0301 basic medicine, medicine.drug_class, 030204 cardiovascular system & hematology, Pharmacology, Antibodies, Monoclonal, Humanized, Monoclonal antibody, Patents as Topic, 03 medical and health sciences, Proprotein Convertase Subtilisin/Kexin 9, 0302 clinical medicine, Drug Discovery, medicine, Animals, Humans, PCSK9 Inhibitors, Dyslipidemias, Alirocumab, business.industry, Anticholesteremic Agents, PCSK9, Antibodies, Monoclonal, Cholesterol, LDL, General Medicine, medicine.disease, 030104 developmental biology, Drug Design, Mutation, Functional activity, lipids (amino acids, peptides, and proteins), Lipid lowering, Proprotein Convertase 9, business, Dyslipidemia
Abstract: Introduction: The identification by Abifadel et al. in 2003 of the first mutations of PCSK9 was the major breakthrough in the cholesterol field that led to a new therapeutic target. This discovery paved the way to new lipid lowering drugs reducing LDL-cholesterol levels through the inhibition of PCSK9. Two anti-PCSK9 monoclonal antibodies have received FDA and EMA approvals: Alirocumab and Evolocumab. Areas covered: This article reviews the different strategies that are pursued to modulate the functional activity of PCSK9 for lowering LDL-cholesterol levels. It also provides a brief overview of the patents related to PCSK9 from 2011 until the end of 2015. This review is addressed to researchers from academia and pharmaceutical companies who are engaged in PCSK9 research/cholesterol regulation. Readers will gain an up-to-date overview of the different strategies that have been investigated to reduce PCSK9, focusing on anti-PCSK9 monoclonal antibodies and the related clinical trials. Expert opinion: Anti-PCSK9 antibodies are a new class of lipid lowering drugs with promising results in reducing LDL-cholesterol. Long-term ongoing studies investigating on a large scale the efficacy and safety of the anti-PCSK9 antibodies and their cardiovascular outcomes are eagerly awaited.
Published: 2016
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21. The U2-spliceosome and its interactors regulate the levels and activity of the LDL receptor in humans

Author: Joost Weyler, Grigorios Panteloglou, B. Van De Sluis, Joel T. Haas, Anne Tybjærg-Hansen, Luisa Vonghia, Ann Verhaegen, Catherine Boileau, Alaa Othman, A. Van Der Graaf, Anne Philippi, Marieke Smit, Sven Francque, Mathilde Varret, Jan Albert Kuivenhoven, Srividya Velagapudi, B.V. Van Rosmalen, L. Van Gaal, Y. Abou Khalil, Justina C. Wolters, Antoine Rimbert, Simon F. Norrelykke, Roger Meier, Bart Staels, Lucia Rohrer, Andrzej J. Rzepiela, Paolo Zanoni, Andreas Geier, Michaela Keel, Valérie Carreau, S.E. Humphries, Michael Stebler, M. Futema, Szymon Stoma, N. Dalila, Melinde Wijers, Nicolette C. A. Huijkman, An Verrijken, Antonio Gallo, Jean-Pierre Rabès, A. von Eckardstein, Silvija Radosavljevic, M. Yalcinkaya, F. van Dijk, and Michele Visentin
Subjects: Spliceosome, Chemistry, LDL receptor, Cardiology and Cardiovascular Medicine, Cell biology
Published: 2020
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22. Postprandial lipid absorption in seven heterozygous carriers of deleterious variants of MTTP in two abetalipoproteinemic families

Author: Jacques Schmitz, Mathilde Di Filippo, Dominique Bonnefont-Rousselot, Sabrina Dumont, Latifa Ferkdadji, Catherine Boileau, Mathilde Varret, V. Boehm, Francisca Joly, Jean-Pierre Rabès, Laurent Abramowitz, Catherine Lenaerts, Marie-Elisabeth Samson-Bouma, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Hôpital Robert Debré, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), CHU Necker - Enfants Malades [AP-HP], Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], 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), Université Paris Descartes - Paris 5 (UPD5), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CarMeN, laboratoire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: Male, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Liver steatosis, 030204 cardiovascular system & hematology, Compound heterozygosity, Microsomal triglyceride transfer protein, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, Child, Fat malabsorption, Sequence Deletion, Nutrition and Dietetics, biology, medicine.diagnostic_test, Postprandial, Middle Aged, Postprandial Period, Abetalipoproteinemia, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Liver, Child, Preschool, Cardiology and Cardiovascular Medicine, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Genotype, Young Adult, 03 medical and health sciences, Malabsorption Syndromes, Internal medicine, Internal Medicine, medicine, Humans, Apolipoproteins B, Polymorphism, Genetic, Triglyceride, business.industry, Infant, Lipid Metabolism, medicine.disease, Genetic hypocholesterolemia, Endocrinology, chemistry, biology.protein, Liver function, Steatosis, Carrier Proteins, Liver function tests, business
Abstract: International audience; BACKGROUND: Abetalipoproteinemia, a recessive disease resulting from deleterious variants in MTTP (microsomal triglyceride transfer protein), is characterized by undetectable concentrations of apolipoprotein B, extremely low levels of low-density lipoprotein cholesterol in the plasma, and a total inability to export apolipoprotein B-containing lipoproteins from both the intestine and the liver. OBJECTIVE: To study lipid absorption after a fat load and liver function in 7 heterozygous relatives from 2 abetalipoproteinemic families, 1 previously unreported. RESULTS: Both patients are compound heterozygotes for p.(Arg540His) and either c.708\₇09del p.(His236Glnfs*11) or c.1344+3\₁344+6del on the MTTP gene. The previously undescribed patient has been followed for 22 years with ultrastructure analyses of both the intestine and the liver. In these 2 families, 5 relatives were heterozygous for p.(Arg540His), 1 for p.(His236Glnfs*11) and 1 for c.1344+3\₁344+6del. In 4 heterozygous relatives, the lipid absorption was normal independent of the MTTP variant. In contrast, in 3 of them, the increase in triglyceride levels after fat load was abnormal. These subjects were additionally heterozygous carriers of Asp2213 APOB in-frame deletion, near the cytidine mRNA editing site, which is essential for intestinal apoB48 production. Liver function appeared to be normal in all the heterozygotes except for one who exhibited liver steatosis for unexplained reasons. CONCLUSION: Our study suggests that a single copy of the MTTP gene may be sufficient for human normal lipid absorption, except when associated with an additional APOB gene alteration. The hepatic steatosis reported in 1 patient emphasizes the need for liver function tests in all heterozygotes until the level of risk is established.
Published: 2019
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23. High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: The French Familial Hypercholesterolemia Registry

Author: Sophie Béliard, Franck Boccara, Bertrand Cariou, Alain Carrié, Xavier Collet, Michel Farnier, Jean Ferrières, Michael Krempf, Noël Peretti, Jean-Pierre Rabès, Mathilde Varret, Alexandre Vimont, Sybil Charrière, Eric Bruckert, D. Angoulvant, S. Béliard, P. Benlian, C. Boileau, F. Boccara, E. Bruckert, B. Cariou, V. Carreau, A. Carrié, S. Charrière, M. Di Filippo, P.H. Ducluzeau, S. Dulong, V. Durlach, M. Farnier, E. Ferrari, J. Ferrières, A. Gallo, J.P. Girardet, R. Hankard, M. Krempf, J.D. Lalau, B. Lefort, J. Lemale, P. Moulin, F. Paillard, N. Peretti, A. Pradignac, Y. Pucheu, J.P. Rabès, S. Saheb, A. Sultan, P. Tounian, R. Valéro, M. Varret, B. Vergès, C. Yelnik, O. Ziegler, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cardiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), CHU Pitié-Salpêtrière [APHP], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Point médical (Dijon), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Hôpital Guillaume et René Laennec - Centre Hospitalier Universitaire de Nantes, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Ambroise Paré, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Tenon [APHP], Rythmes Biologiques et Cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Nutrition, croissance et cancer (U 1069) (N2C), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Maladies Métaboliques et Endocrinologie, Université de la Méditerranée - Aix-Marseille 2, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), ANR: 16-RHUS-0007,CHOPIN,Recherches Hospitalo-universitaires en santé, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Epidémiologie, Economie de la Santé et Santé Publique, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service d' Endocrinologie, Centre Hospitalier Universitaire de Grenoble, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), CHU Saint-Antoine [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), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Hôpital Ambroise Paré [AP-HP], Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Tenon [AP-HP], SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), ANR-16-RHUS-0007, ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Fattouma Bourguiba [Monastir] (HFB), Unité de recherche de l'institut du thorax (ITX-lab), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière]
Subjects: Male, coronary-artery-disease, Heredity, Time Factors, Heart disease, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Coronary artery disease, 0302 clinical medicine, Interquartile range, Recurrence, Risk Factors, Secondary Prevention, 030212 general & internal medicine, Myocardial infarction, Registries, panel, risk, education.field_of_study, Anticholesteremic Agents, PCSK9 Inhibitors, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Cardiovascular disease, myocardial-infarction, 3. Good health, Pedigree, Phenotype, Treatment Outcome, Cardiovascular Diseases, Drug Therapy, Combination, Female, France, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, guidance, management, Adult, medicine.medical_specialty, Heterozygote, Registry, Serine Proteinase Inhibitors, european atherosclerosis society, Population, Down-Regulation, Risk Assessment, Hyperlipoproteinemia Type II, Cardiovascular events, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, Cardiovascular recurrences, esc/eas guidelines, Unstable angina, business.industry, cholesterol, Percutaneous coronary intervention, Cholesterol, LDL, medicine.disease, heart-disease, Cardiovascular System & Cardiology, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Biomarkers
Abstract: International audience; Background and aims: Cardiovascular risk is high in heterozygous familial hypercholesterolemia (HeFH). The objective of this study was to describe recurrent cardiovascular events in selected patients with HeFH attending lipid clinics in France. Methods: We included 781 patients with a clinical (Dutch Lipid Clinic Network score \textgreater= 6) or genetic diagnosis of HeFH who had experienced a first cardiovascular event (myocardial infarction, percutaneous coronary intervention or coronary bypass, unstable angina, stroke, peripheral arterial revascularization or cardiovascular death) and were enrolled in the French Familial Hypercholesterolemia Registry (November 2015 to March 2018). Results: The first cardiovascular event occurred at the mean age of 47 years (interquartile range 39-55) in a predominantly male population (72%); 48% of patients were on statin therapy. Overall, 37% of patients had at least one recurrent cardiovascular event (mean of 1.8 events per patient), of which 32% occurred in the 12 months after the index event; 55% of events occurred \textgreater 3 years after the first event. Mean LDL-C at the last clinic visit was 144 +/- 75 mg/dL (132 +/- 69 mg/dL for patients on high-potency statin therapy and 223 +/- 85 mg/dL for untreated patients). Conclusions: The rate of recurrent cardiovascular events was high in French patients with HeFH in secondary prevention. The detection of FH during childhood is crucial to prevent CV events at a young age by early initiating statin therapy. There is a clear urgent need to expand the actual very small target population which can be treated with the PCSK9 inhibitor in France.
Published: 2018
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24. 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

25. Familial hypercholesterolemia: experience from France

Author: Jean-Pierre Rabès, Sophie Béliard, Alain Carrié, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), UFR des Sciences de la Santé Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Service de Biochimie Endocrinienne et Oncologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), 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)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: 0301 basic medicine, Apolipoprotein B, cascade screening, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Familial hypercholesterolemia, Cascade screening, 030204 cardiovascular system & hematology, French registry, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, molecular diagnosis, Genetics, Medicine, apolipoprotein B, Humans, Genetic Predisposition to Disease, Molecular Biology, Ldl cholesterol, Nutrition and Dietetics, biology, familial hypercholesterolemia, business.industry, LDL Receptor, nutritional and metabolic diseases, Cell Biology, medicine.disease, gene score, 3. Good health, 030104 developmental biology, LDL receptor, Mutation (genetic algorithm), LDL cholesterol, Mutation, biology.protein, Proprotein convertase subtilisin, lipids (amino acids, peptides, and proteins), France, Cardiology and Cardiovascular Medicine, business, kexin type 9
Abstract: International audience; Purpose of review We provide an overview of molecular diagnosis for familial hypercholesterolemia in France including descriptions of the mutational spectrum, polygenic susceptibility and perspectives for improvement in familial hypercholesterolemia diagnosis. Recent findings Molecular testing for familial hypercholesterolemia is recommended for patients with a LDL-cholesterol level above 190mg/dl (adults) associated with criteria related to personal and family history of hypercholesterolemia and premature cardiovascular disease. Among the 3381 index cases included with these characteristics in the French registry for familial hypercholesterolemia, 2054 underwent molecular diagnosis and 1150 (56%) were found to have mutations (93.5% in LDL Receptor (LDLR), 4.7% in apolipoprotein B and 1.8% in Proprotein convertase subtilisin/kexin type 9). A total of 416 different pathogenic variants were found in the LDLR gene. Based on gene score calculation, a polygenic origin may be suggested in 36% of nonmutated patients. Involvement of genetic counselors and education of healthcare professionals for genetics of familial hypercholesterolemia are underway with the aim of improving the efficiency of the diagnosis. Summary Genetic cascade screening for familial hypercholesterolemia is currently implemented in France with the complexity to address the diversity of its molecular cause in index cases. Optimization of patient care pathways is critical to improve both the rate of diagnosis and the management of familial hypercholesterolemia patients.
Published: 2018
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26. New Sequencing technologies help revealing unexpected mutations in Autosomal Dominant Hypercholesterolemia

Author: Jean-Pierre Rabès, Mathilde Varret, Catherine Boileau, Marianne Abifadel, Eric Bruckert, Gina M. Peloso, Ali Ben-Djoudi-Ouadda, Josée Hamelin, Nabil G. Seidah, Youmna Ghaleb, Nathan O. Stitziel, Valérie Carreau, Petra El Khoury, Sandy Elbitar, Delia Susan-Resiga, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Saint-Joseph de Beyrouth (USJ), Université Paris Diderot - Paris 7 (UPD7), Université de Montréal (UdeM), Boston University [Boston] (BU), The McDonnell Genome Institute (MGI), Washington University in Saint Louis (WUSTL), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, Heterozygote, Apolipoprotein B, lcsh:Medicine, 030204 cardiovascular system & hematology, medicine.disease_cause, Compound heterozygosity, Article, Hyperlipoproteinemia Type II, 03 medical and health sciences, Exon, 0302 clinical medicine, Chromosome Segregation, medicine, Humans, Family, lcsh:Science, Gene, Exome, Exome sequencing, Apolipoproteins B, Genetics, Mutation, Multidisciplinary, biology, lcsh:R, nutritional and metabolic diseases, High-Throughput Nucleotide Sequencing, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Pedigree, 030104 developmental biology, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, LDL receptor, biology.protein, lcsh:Q, lipids (amino acids, peptides, and proteins), Female, Proprotein Convertase 9
Abstract: Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated LDL-C levels leading to coronary heart disease. Four genes are implicated in ADH: LDLR, APOB, PCSK9 and APOE. Our aim was to identify new mutations in known genes, or in new genes implicated in ADH. Thirteen French families with ADH were recruited and studied by exome sequencing after exclusion, in their probands, of mutations in the LDLR, PCSK9 and APOE genes and fragments of exons 26 and 29 of APOB gene. We identified in one family a p.Arg50Gln mutation in the APOB gene, which occurs in a region not usually associated with ADH. Segregation and in-silico analysis suggested that this mutation is disease causing in the family. We identified in another family with the p.Ala3396Thr mutation of APOB, one patient with a severe phenotype carrying also a mutation in PCSK9: p.Arg96Cys. This is the first compound heterozygote reported with a mutation in APOB and PCSK9. Functional studies proved that the p.Arg96Cys mutation leads to increased LDL receptor degradation. This work shows that Next-Generation Sequencing (exome, genome or targeted sequencing) are powerful tools to find new mutations and identify compound heterozygotes, which will lead to better diagnosis and treatment of ADH.
Published: 2018
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27. PCSK9 polymorphism in a Tunisian cohort: Identification of a new allele, L8, and association of allele L10 with reduced coronary heart disease risk

Author: Mathilde Varret, Khaldoun Ben Hamda, Mohamed Yahia Hrira, Afef Slimani, Faouzi Maatouk, Walid Jomaa, Catherine Boileau, Marianne Abifadel, Jean-Pierre Rabès, Mustapha Rouis, Mohamed Najah, Mohamed Naceur Slimane, Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ministries of Higher Education and Scientific Research (Project PHC-Utique du CMCU, comite mixte pour la cooperation universitaire Franco-Tunisien) [10G0812], L'Agence Nationale de la Recherche [ANR-08-GENO-002-01], Fondation-Leducq [13CVD03], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, medicine.medical_specialty, Tunisia, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Coronary Artery Disease, c.61\₆3dupCTG, Biology, Polymorphism, Single Nucleotide, Gastroenterology, White People, Coronary artery disease, Polymorphism (computer science), Internal medicine, Genotype, medicine, Humans, Allele, Molecular Biology, Alleles, Genetic Association Studies, Aged, Sequence Deletion, Genetics, PCSK9, Serine Endopeptidases, Cell Biology, Middle Aged, medicine.disease, Coronary arteries, Stenosis, medicine.anatomical_structure, PCSK9 gene, Case-Control Studies, Cohort, Regression Analysis, rs72555377, Female, Proprotein Convertases, Proprotein Convertase 9
Abstract: International audience; The c.61\₆3dupCTG (L10) allele of rs72555377 polymorphism in PCSK9 has been reported to be associated with low-density lipoprotein-cholesterol (LDL-C) levels and with a decreased risk of coronary artery disease (CAD). We investigated the effect of two known alleles for rs72555377, L10 and L11, on the risk of CAD in a Tunisian cohort (218 patients diagnosed by angiography and 125 control subjects). Two subgroups of patients were defined by their level of stenosis: >= 50% for CAD and = 50% in two or three major coronary arteries (0.210 vs 0.125, p = 0.028). Multiple regression analysis showed that the L10 allele was significantly associated with a reduced risk of CAD (p = 0.049, OR = 0.51[0.26-1.00]), and with its reduced severity (p = 0.045, OR = 0.44[0.20-0.98]). The L10 allele is associated with a reduced risk and severity of CAD, seemingly independently of its LDL-lowering effect, suggesting a direct effect of PCSK9 on atherogenesis.
Published: 2015
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28. Genetic diagnosis of familial hypercholesterolemia is associated with a premature and high coronary heart disease risk

Author: Jean-Bernard Ruidavets, Jean Ferrières, Vanina Bongard, Florent Séguro, Dorota Taraszkiewicz, and Jean-Pierre Rabès
Subjects: Adult, Male, medicine.medical_specialty, DNA Mutational Analysis, Clinical Investigations, Coronary Disease, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Gastroenterology, Risk Assessment, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Medicine, Humans, In patient, 030212 general & internal medicine, Genetic Testing, Prospective Studies, medicine.diagnostic_test, business.industry, Pathogenic mutation, Incidence, Autosomal dominant trait, General Medicine, Cholesterol, LDL, DNA, Middle Aged, medicine.disease, Coronary heart disease, Mutation (genetic algorithm), Mutation, Female, France, Cardiology and Cardiovascular Medicine, business, Genetic diagnosis, Lipid profile, Follow-Up Studies
Abstract: BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant disease associated with premature coronary heart disease (CHD). Studies tend to show that patients with FH associated with an identified mutation (mutation+ FH) are at higher risk than patients without an identified mutation (mutation– FH). We compared the clinical and biological profile and the risk of CHD in patients with mutation+ FH and mutation– FH. HYPOTHESIS: In addition to LDL‐C, a pathogenic mutation predicts premature CHD in FH. METHODS: We successively included all patients with suspected FH (LDL‐C > 190 mg/dL if age > 18 years; LDL‐C > 160 mg/dL if age
Published: 2017

29. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia

Author: Wilfried Le Goff, Josée Hamelin, Jean-Pierre Rabès, Zélie Julia, Dominique Bonnefont-Rousselot, Valérie Carreau, Olivier Meilhac, Mathilde Varret, Marianne Abifadel, Philippe Couvert, Nabil G. Seidah, Laurent Tosolini, Alain Carrié, John Chapman, Suzanne Benjannet, Eric Bruckert, Maryse Guerin, Jean-Baptiste Michel, Catherine Boileau, and Annik Prat
Subjects: Male, Paris, Apolipoprotein B, DNA Mutational Analysis, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Transfection, medicine.disease_cause, Hyperlipoproteinemia Type II, 03 medical and health sciences, PCSK9 Gene, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Apolipoproteins B, 030304 developmental biology, Genetics, 0303 health sciences, Mutation, biology, PCSK9, Cholesterol, HDL, Serine Endopeptidases, nutritional and metabolic diseases, Hep G2 Cells, Proprotein convertase, medicine.disease, Phenotype, Pedigree, HEK293 Cells, Receptors, LDL, LDL receptor, biology.protein, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Biomarkers
Abstract: Background The identification of mutations in PCSK9 (proprotein convertase subtilisin kexin9) in autosomal dominant hypercholesterolemia (ADH), has revealed the existence of a new player in cholesterol homeostasis. PCSK9 has been shown to enhance the degradation of the LDL receptor (LDLR) at the cell surface. Gain-of-function mutations of PCSK9 induce ADH and are very rare, but their identification is crucial in studying PCSK9's role in hypercholesterolemia, its detailed trafficking pathway and its impact on the LDLR. Methods In order to identify new mutations and understand the exact mechanisms of action of mutated PCSK9, PCSK9 was sequenced in 75 ADH patients with no mutations in the LDLR or APOB genes. Functional analyses in cell culture were conducted and the impact of novel PCSK9 mutations on the quantitative and qualitative features of lipoprotein particles and on the HDL-mediated cellular cholesterol efflux was studied. Results Among these 75 ADH probands with no mutations in the LDLR or APOB genes, four gain-of-function mutations of PCSK9 were identified, of which two were novel: the p.Leu108Arg and the p.Asp35Tyr substitutions. In vitro studies of their consequences on the activity of PCSK9 on cell surface levels of LDLR showed that the p.Leu108Arg mutation clearly results in a gain-of-function, while the p.Asp35Tyr mutation created a novel Tyr-sulfation site, which may enhance the intracellular activity of PCSK9. Conclusion These data further contribute to the characterization of PCSK9 mutations and to better understanding of the impact on cholesterol metabolism of this new therapeutic target.
Published: 2012
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30. Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients

Author: Asma Omezzine, Lamia Rebhi, Faouzi Maatouk, Imen Jguirim, Maha Kacem, Mohamed Najah, Marianne Abifadel, Awatef Jelassi, Afef Slimani, Jean-Pierre Rabès, Catherine Boileau, Mustapha Rouis, Mathilde Varret, Khaldoun Ben Hamda, Mohamed Naceur Slimane, Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tunisian Ministry of Higher Education and Scientific Research [PHC-Utique 10G0812 du CMCU], French Ministry of Higher Education and Scientific Research [PHC-Utique 10G0812 du CMCU], L'Agence Nationale de la Recherche [ANR-08-GENO-002-01], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, LDLR gene, Apolipoprotein E, Heterozygote, Tunisia, Adolescent, Familial hypercholesterolemia, Mutation, Missense, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Frameshift mutation, Hyperlipoproteinemia Type II, PCSK9 Gene, Apolipoproteins E, Phenotypic variability, Genetic variation, medicine, Humans, Missense mutation, Child, Frameshift Mutation, Gene, Genetics, Mutation, Homozygote, Serine Endopeptidases, Cholesterol, LDL, Middle Aged, Molecular biology, Pedigree, Phenotype, Receptors, LDL, PCSK9 gene, Child, Preschool, LDL receptor, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine
Abstract: Background Autosomal dominant hypercholesterolemia (ADH) is commonly caused by mutations in the low-density lipoprotein (LDL) receptor gene ( LDLR ), in the apolipoprotein B-100 gene ( APOB ), or in the proprotein convertase subtilisin kexine 9 gene ( PCSK9 ). ADH subjects carrying a mutation in LDLR present highly variable plasma LDL-cholesterol (LDL-C). This variability might be due to environmental factors or the effect of some modifying genes such as PCSK9 and APOE . Aims We investigated the molecular basis of thirteen Tunisian ADH families and attempted to determine the impact of PCSK9 and APOE gene variations on LDL-cholesterol levels and on the variable phenotypic expression of the disease. Methods and results Fifty six subjects were screened for mutations in the LDLR gene through direct sequencing. The causative mutation was found to segregate with the disease in each family and a new frameshift mutation, p.Met767CysfsX21, was identified in one family. The distribution of total- and LDL-cholesterol levels, adjusted for age and gender, among homozygous and heterozygous ADH patients varied widely. Within seven families, nine subjects presented low LDL-cholesterol levels despite carrying a mutation in the LDLR gene. To identify the molecular actors underlying this phenotypic variability, the PCSK9 gene was screened using direct sequencing and/or enzymatic restriction analysis, and the apo E genotypes were determined. A new missense variation (p.Pro174Ser) in the PCSK9 gene was identified and characterized as a new putative loss-of-function mutation. Conclusion Genetic variations in PCSK9 and APOE genes could explain only part of the variability observed in the phenotypic expression in Tunisian ADH patients carrying mutations in the LDLR gene. Other genetic variants and environmental factors very probably act to fully explain this phenotypic variability.
Published: 2012
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31. A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1

Author: Alice Marques-Pinheiro, Marianne Abifadel, Claudine Junien, Yassine Zair, Mathilde Varret, Delphine Allard, D. Erlich, Michel Krempf, Arnold Munnich, M. Marduel, Jean-Philippe Jais, Jean Weissenbach, Catherine Boileau, Martine Devillers, Ludovic Villéger, Maryse Guerin, Jean-Pierre Rabès, Université Paris Descartes - Paris 5 ( UPD5 ), and Université Paris Descartes - Paris 5 (UPD5)
Subjects: Adult, Male, Adolescent, Apolipoprotein B, Genome-wide association study, Locus (genetics), Article, Hyperlipoproteinemia Type II, Young Adult, Gene mapping, Genetics, Humans, Coding region, Genetic Predisposition to Disease, Child, Gene, Genetics (clinical), lipoprotein metabolism, Aged, 80 and over, Family Health, hypercholesterolemia, biology, Genetic heterogeneity, Chromosome Mapping, Middle Aged, Pedigree, Child, Preschool, LDL receptor, biology.protein, Female, lipids (amino acids, peptides, and proteins), genetic mapping, France, Lod Score, Chromosomes, Human, Pair 16, Genome-Wide Association Study
Abstract: Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated increase in plasmatic low-density lipoprotein (LDL) cholesterol levels associated with high risk of premature cardiovascular disease. Mutations in LDLR, APOB, and PCSK9 genes have been shown to cause ADH. We now report further genetic heterogeneity of ADH through the study of a large French family in which the involvement of these three genes was excluded. A genome-wide scan mapped the disease-causing gene, named HCHOLA4, at 16q22.1 in a 7.89-Mb interval containing 154 genes with a maximum LOD score of 3.9. To reduce the linked region, we genotyped 18 smaller non-LDLR/non-APOB/non-PCSK9-ADH families at the HCHOLA4 locus. Six families did not exclude linkage to the locus, but none allowed reduction of the disease interval. The 154 regional genes were sorted according to the function of the encoded protein and tissue expression profiles, and 57 genes were analyzed through sequencing of their coding region and close flanking intronic parts. No disease-causing mutation was identified in these families, particularly in the LCAT gene. Finally, our results also show the existence of other ADH genes as nine families were neither linked to LDLR, APOB, and PCSK9 genes nor to the new HCHOLA4 locus.
Published: 2010
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32. The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

Author: Hermine Aydénian, Jean-Pierre Rabès, Marie-Hélène Gannagé-Yared, Ghada Beaino, Antoine Sarkis, Mathilde Varret, Georges Halaby, Sandra Corbani, Marianne Abifadel, Selim Jambart, Catherine Boileau, Claudine Junien, Arnold Munnich, and Nabiha Salem
Subjects: Apolipoprotein B, Population, Mutation, Missense, Familial hypercholesterolemia, Hyperlipoproteinemia Type II, Exon, Genetics, medicine, Humans, Missense mutation, Lebanon, education, Genetics (clinical), Family Health, education.field_of_study, biology, PCSK9, Serine Endopeptidases, nutritional and metabolic diseases, Cholesterol, LDL, medicine.disease, Receptors, LDL, Codon, Nonsense, Mutation, LDL receptor, biology.protein, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Proprotein Convertase 9, Founder effect
Abstract: Autosomal dominant hypercholesterolemia (ADH), a major risk for coronary heart disease, is associated with mutations in the genes encoding the low-density lipoproteins receptor (LDLR), its ligand apolipoprotein B (APOB) or PCSK9 (Proprotein Convertase Subtilin Kexin 9). Familial hypercholesterolemia (FH) caused by mutation in the LDLR gene is the most frequent form of ADH. The incidence of FH is particularly high in the Lebanese population presumably as a result of a founder effect. In this study we characterize the spectrum of the mutations causing FH in Lebanon: we confirm the very high frequency of the LDLR p.Cys681X mutation that accounts for 81.5 % of the FH Lebanese probands recruited and identify other less frequent mutations in the LDLR. Finally, we show that the p.Leu21dup, an in frame insertion of one leucine to the stretch of 9 leucines in exon 1 of PCSK9, known to be associated with lower LDL-cholesterol levels in general populations, is also associated with a reduction of LDL-cholesterol levels in FH patients sharing the p.C681X mutation in the LDLR. Thus, by studying for the first time the impact of PCSK9 polymorphism on LDL-cholesterol levels of FH patients carrying a same LDLR mutation, we show that PCSK9 might constitute a modifier gene in familial hypercholesterolemia. © 2009 Wiley-Liss, Inc.
Published: 2009
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33. Limited mutational heterogeneity in the LDLR gene in familial hypercholesterolemia in Tunisia

Author: A.M. Abid, Mathilde Varret, Imen Jguirim, Awatef Jelassi, L. Boughamoura, Mohamed Najah, Jean-Pierre Rabès, Mohamed Naceur Slimane, F. Maatouk, Catherine Boileau, and M. Rouis
Subjects: Adult, Male, Heterozygote, Tunisia, Adolescent, DNA Mutational Analysis, Population, Nonsense mutation, Familial hypercholesterolemia, Biology, Frameshift mutation, Hyperlipoproteinemia Type II, Exon, medicine, Humans, Missense mutation, education, Aged, Family Health, Genetics, education.field_of_study, Polymorphism, Genetic, Autosomal dominant trait, Exons, medicine.disease, Pedigree, Receptors, LDL, Mutation, Mutation (genetic algorithm), Female, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine
Abstract: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the low-density lipoprotein receptor ( LDLR ), apolipoprotein B ( APOB ), and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) genes. In previous studies, we have identified novel mutations in Tunisian FH families. In this study, we have extended our investigation to additional families. Five unrelated probands were screened for mutations in the LDLR and APOB genes, using direct sequencing and enzymatic restriction. We identified two novel LDLR mutations: a missense mutation in exon 7: p.Gly343Cys (c.1027G>T), and a nonsense mutation in exon 17: p.Lys816X (c.2446A>T). Using the PolyPhen and SIFT prediction computer programs the p.Gly343Cys is predicted to have a deleterious effect on LDL receptor activity. The missense mutation we found in exon 3, p.Cys89Trp (c.267C>G), has previously been identified in patients from United Kingdom and Spain, and is reported here for the first time in the Tunisian population. Finally, the framshift mutation in exon 10, p.Ser493ArgfsX44, is reported here for the fourth and fifth time in Tunisian families. The latter is the most frequent FH-causing mutation in Tunisia. These LDLR gene mutations enrich the spectrum of mutations causing FH in the Tunisian population. The framshift mutation, p.Ser493ArgfsX44, seems to be a founder mutation in this population.
Published: 2009
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34. Genetic heterogeneity of autosomal dominant hypercholesterolemia

Author: Marianne Abifadel, Catherine Boileau, Mathilde Varret, and Jean-Pierre Rabès
Subjects: Genetics, Mutation, Apolipoprotein B, Genetic heterogeneity, PCSK9, Serine Endopeptidases, Biology, medicine.disease_cause, Hyperlipoproteinemia Type II, Genetic Heterogeneity, PCSK9 Gene, LDL receptor, biology.protein, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Proprotein Convertase 9, Gene, Genetics (clinical)
Abstract: Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated elevation of plasmatic low-density lipoprotein cholesterol associated with high risk of premature cardiovascular complications. More than 1000 mutations in the LDLR gene and 9 in the APOB gene have been implicated. We have shown further heterogeneity with the discovery of missense mutations in the PCSK9 gene resulting in ADH. Different studies have tried to evaluate the respective contribution of mutations in each gene to the disease, but results were not always in agreement. After a brief overview of mutations reported for each gene, strategies and results of these different studies are reviewed and analyzed. Altogether, numerous reports give evidence for the existence of a greater level of genetic heterogeneity in ADH and the involvement of still unknown genes.
Published: 2007
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35. C57BL/6J and A/J Mice Fed a High-Fat Diet Delineate Components of Metabolic Syndrome*

Author: Catherine Gallou-Kabani, Alexandre Vigé, Jean-Pierre Rabès, Christiane Larue-Achagiotis, M. S. Gross, Daniel Tomé, Claudine Junien, Jean-Philippe Jais, and Catherine Boileau
Subjects: Blood Glucose, Leptin, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Type 2 diabetes, Biology, Cohort Studies, Fatty Acids, Monounsaturated, Impaired glucose tolerance, Eating, Mice, Endocrinology, Insulin resistance, Pregnancy, Internal medicine, Diabetes mellitus, medicine, Hyperinsulinemia, Animals, Insulin, Obesity, Triglycerides, Metabolic Syndrome, Glucose tolerance test, Nutrition and Dietetics, medicine.diagnostic_test, Body Weight, Glucose Tolerance Test, medicine.disease, Dietary Fats, Specific Pathogen-Free Organisms, Mice, Inbred C57BL, Disease Models, Animal, Cholesterol, Diabetes Mellitus, Type 2, Body Composition, Female, Metabolic syndrome, medicine.symptom, Weight gain
Abstract: Objective: The aim of this study was to assess the suitability of A/J and C57BL/6J mice of both sexes as models of some components of the human metabolic syndrome (MetS) under nutritional conditions more comparable with the actual worldwide diet responsible for the increased incidence of the MetS. Research Methods: We fed large cohorts (n = 515) of two strains of mice, A/J and the C57BL/6J, and of both sexes a high-fat diet (HFD; 60% fat) that, in contrast with most previous reports using saturated fats, was enriched in mono- and polyunsaturated fatty acids, thus more closely mimicking most Western diets, or a control diet (10% fat), for 20 weeks. Results: In sharp contrast to previous reports, weight gain and hyperleptinemia were similar in both strains and sexes. Hyperinsulinemia, glucose tolerance, insulin resistance, and hypercholesterolemia were observed, although with important differences between strains and sexes. A/J males displayed severely impaired glucose tolerance and insulin resistance. However, in contrast with C57BL6/J mice, which displayed overt type 2 diabetes, A/J mice of both sexes remained normoglycemic. Discussion: With important differences in magnitude and time course, the phenotypic and metabolic characteristics of both strains and both sexes on this HFD demonstrate that these models are very useful for identifying the mechanisms underlying progression or resistance to subsequent type 2 diabetes.
Published: 2007
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36. Resistance to high-fat diet in the female progeny of obese mice fed a control diet during the periconceptual, gestation, and lactation periods

Author: M. S. Gross, Claudine Junien, Jean-Philippe Jais, Catherine Gallou-Kabani, Catherine Boileau, Alexandre Vigé, Jean-Pierre Rabès, and Jamilla Fruchart-Najib
Subjects: Male, medicine.medical_specialty, Physiology, Endocrinology, Diabetes and Metabolism, Hyperphagia, Overweight, Biology, Weight Gain, Fetal Development, Mice, Sex Factors, Pregnancy, Physiology (medical), Internal medicine, Lactation, medicine, Animals, Homeostasis, Insulin, Obesity, Diet, Fat-Restricted, Metabolic Syndrome, Fetus, nutritional and metabolic diseases, High fat diet, Glucose Tolerance Test, Lipid Metabolism, medicine.disease, Dietary Fats, Mice, Inbred C57BL, Pregnancy Complications, Glucose, medicine.anatomical_structure, Endocrinology, Animals, Newborn, Fertilization, Gestation, Female, Disease Susceptibility, medicine.symptom, Metabolic syndrome, Energy Intake
Abstract: With the worldwide epidemic of metabolic syndrome (MetS), the proportion of women that are overweight/obese and overfed during pregnancy has increased. The resulting abnormal uterine environment may have deleterious effects on fetal metabolic programming and lead to MetS in adulthood. A balanced/restricted diet and/or physical exercise often improve metabolic abnormalities in individuals with obesity and type 2 diabetes mellitus (T2D). We investigated whether reducing fat intake during the periconceptual/gestation/lactation period in mothers with high-fat diet (HFD)-induced obesity could be used to modify fetal/neonatal MetS programming positively, thereby preventing MetS. First generation (F1) C57BL/6J female mice with HFD-induced obesity and T2D were crossed with F1 males on control diet (CD). These F1 females were switched to a CD during the periconceptual/gestation/lactation period. At weaning, both male and female second generation (F2) mice were fed a HFD. Weight, caloric intake, lipid parameters, glucose, and insulin sensitivity were assessed. Sensitivity/resistance to the HFD differed significantly between generations and sexes. A similar proportion of the F1 and F2 males (80%) developed hyperphagia, obesity, and T2D. In contrast, a significantly higher proportion of the F2 females (43%) than of the previous F1 generation (17%) were resistant ( P < 0.01). Despite having free access to the HFD, these female mice were no longer hyperphagic and remained lean, with normal insulin sensitivity and glycemia but mild hypercholesterolemia and glucose intolerance, thus displaying a “satiety phenotype.” This suggests that an appropriate dietary fatty acid profile and intake during the periconceptual/gestation/lactation period helps the female offspring to cope with deleterious intrauterine conditions.
Published: 2007
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37. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody

Author: Bertrand Cariou, Yassine Zair, Hisashi Makino, Paul N. Hopkins, Alain Carrié, Sara Hamon, Bernard Chanu, Michel Farnier, Kunimasa Yagi, Hiroshi Mabuchi, Yee P. Teoh, Michel Krempf, Matthieu Pichelin, Neil Stahl, Johanna Mendoza, George D. Yancopoulos, Masakazu Yamagishi, Charles van Heyningen, Catherine Boileau, Marianne Abifadel, A. David Marais, Sigrid W. Fouchier, Barbara Sjouke, Valérie Carreau, Masa-aki Kawashiri, Eric Bruckert, Scott Mellis, Mafalda Bourbon, Hayato Tada, Yoshihiro Miyamoto, Yunling Du, Jean-Pierre Rabès, Gary Swergold, Joep C. Defesche, Mariko Harada-Shiba, Ichiro Kishimoto, Shoji Katsuda, Trond P. Leren, Handrean Soran, Atsushi Nohara, Gérald Luc, Gilles Lambert, Cardiovascular Genetics Division, University of Utah School of Medicine [Salt Lake City], Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Service de Médecine Interne, PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Vascular Medicine, Emma Children’s Hospital Academic Medical Centre, National cerebral and cardiovascular center research institute, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie et de Génétique Moléculaire, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Biochimie Endocrinienne et Oncologique [CHU Pitié-Salpêtrière], Point médical (Dijon), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Saint-Joseph de Beyrouth (USJ), Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, diabétologie et nutrition, Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], 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), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Université Paris Diderot - Paris 7 (UPD7)-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), Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Université de Lorraine (UL)-Université de Strasbourg (UNISTRA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), ACS - Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, Medical Biochemistry, Graduate School, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Apolipoprotein B, [SDV]Life Sciences [q-bio], alirocumab, Coronary Artery Disease, Bioinformatics, Gastroenterology, Doenças Cardio e Cérebro-vasculares, PCSK9, Hypercapnia, Coronary artery disease, Cardiovascular Disease, Clinical endpoint, Genetics (clinical), education.field_of_study, biology, Serine Endopeptidases, Antibodies, Monoclonal, PCSK9 protein, cardiovascular diseases, clinical trial, genetics, human, hypercholesterolemia, Middle Aged, Clinical Trial, 3. Good health, Cardiovascular Diseases, Alimentation et Nutrition, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Original Article, Female, Proprotein Convertases, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Heterozygote, Adolescent, Population, Hypercholesterolemia, Antibodies, Monoclonal, Humanized, Hyperlipoproteinemia Type II, Double-Blind Method, Internal medicine, medicine, Genetics, Food and Nutrition, Humans, education, Alirocumab, Aged, business.industry, Cholesterol, LDL, medicine.disease, Clinical trial, Receptors, LDL, Mutation, biology.protein, Age of onset, business
Abstract: Supplemental Digital Content is available in the text., Background— Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. Methods and Results— We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P
Published: 2015
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38. [Anti-PCSK9 in coronary artery disease: genetic progress, therapeutic approaches]

Author: Marianne, Abifadel, Youmna, Ghaleb, Sandy, Elbitar, Petra, El Khoury, Jean-Pierre, Rabès, Mathilde, Varret, and Catherine, Boileau
Subjects: Therapies, Investigational, Serine Endopeptidases, Antibodies, Monoclonal, Humans, Coronary Artery Disease, Genetic Therapy, Proprotein Convertases, Proprotein Convertase 9, RNA, Small Interfering
Published: 2015

39. PC9, A New Actor in Autosomal Dominant Hypercholesterolemia

Author: Mathilde Varret, Jean-Pierre Rabès, Delphine Allard, and Marianne Abifadel
Subjects: Genetics, business.industry, Medicine, business, Genetics (clinical)
Published: 2005
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40. Familial hypercholesterolemia in Morocco: first report of mutations in the LDL receptor gene

Author: R. Chater, A. Adlouni, Karima Aït Chihab, Josep Ribalta, Joan-Carles Vallvé, Mohammed Loutfi, Catherine Boileau, Faiza Bennis, Luis Masana, Mariame El Messal, Jean-Pierre Rabès, Mathilde Varret, Anass Kettani, and A. Hafidi
Subjects: Adult, Male, Adolescent, Apolipoprotein B, DNA Mutational Analysis, Population, Familial hypercholesterolemia, Biology, medicine.disease_cause, Hyperlipoproteinemia Type II, Exon, Genetics, medicine, Humans, Missense mutation, Child, education, Gene, Genetics (clinical), Mutation, education.field_of_study, nutritional and metabolic diseases, Middle Aged, medicine.disease, Molecular biology, Morocco, Receptors, LDL, LDL receptor, biology.protein, Female, lipids (amino acids, peptides, and proteins)
Abstract: Familial hypercholesterolemia (FH) is a genetic disorder mainly caused by defects in the low-density lipoprotein receptor (LDLR) gene, although it can also be due to alterations in the gene encoding apolipoprotein B (familial defective apoB or FDB) or in other unidentified genes. In Morocco, the molecular basis of FH is unknown. To obtain information on this issue, 27 patients with FH from eight unrelated families were analyzed by screening the LDLR (PCR-SSCP and Southern blot) and apoB genes (PCR and restriction enzyme digestion analysis). None of the patients carried either the R3500Q or the R3531C mutation in the apoB gene. By contrast, seven mutations in the LDLR gene were identified, including five missense mutations on exons 4, 6, 8, and 14 (C113R, G266C, A370T, P664L, C690S) and two large deletions (FH Morocco-1 and FH Morocco-2). The two major rearrangements and the missense mutation G266C are novel mutations and could well be causative of FH in the Moroccan population. This study has yielded preliminary information on the mutation spectrum of the LDLR gene among patients with FH in Morocco.
Published: 2003
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41. Intronic mutations outside of Alu -repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia

Author: Yves Reznik, Dorothée Briffaut, Alexandre Fredenrich, Sabine Amsellem, Jean-Pierre Rabès, J.P. Girardet, Pascale Benlian, Jean Luc De Gennes, Michel Krempf, Eric Brukert, Alain Carrié, Bernard Vialettes, and Philippe Moulin
Subjects: Genetics, education.field_of_study, Base Sequence, Population, Intron, Alu element, Locus (genetics), Exons, Biology, Molecular biology, Introns, Hyperlipoproteinemia Type II, Exon, Receptors, LDL, Polypyrimidine tract, Mutation, Humans, Allelic heterogeneity, Allele, education, Genetics (clinical), DNA Primers, Repetitive Sequences, Nucleic Acid
Abstract: Familial hypercholesterolemia (FH), a frequent monogenic condition complicated by premature cardiovascular disease, is characterized by high allelic heterogeneity at the low-density lipoprotein receptor (LDLR) locus. Despite more than a decade of genetic testing, knowledge about intronic disease-causing mutations has remained limited because of lack of available genomic sequences. Based on the finding from bioinformatic analysis that Alu repeats represent 85% of LDLR intronic sequences outside exon-intron junctions, we designed a strategy to improve the exploration of genomic regions in the vicinity of exons in 110 FH subjects from an admixed population. In the first group of 42 patients of negative mutation carriers, as previously established by former screening strategies (denaturing gradient gel electrophoresis, DNA sequencing with former primers overlapping splice-sites, Southern Blotting), about half (n=22) were found to be carriers of at least one heterozygous mutation. Among a second group of 68 newly recruited patients, 27% of mutation carriers (n=37) had a splicing regulatory mutation. Overall, out of the 54 mutations identified, 13 were intronic, and 18 were novel, out of which nearly half were intronic. Two novel intronic mutations (IVS8–10G→A within the polypyrimidine tract and IVS7+10G→A downstream of donor site) might create potential aberrant splice sites according to neural-network computed estimation, contrary to 31 common single nucleotide variations also identified at exon-intron junctions. This new strategy of detecting the most likely disease-causing LDLR mutations outside of Alu-rich genomic regions reveals that intronic mutations may have a greater impact than previously reported on the molecular basis of FH. Electronic supplementary material to this paper can be obtained by using the Springer Link server located at http://dx.doi.org/10.1007/s00439-002-0813-4
Published: 2002
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42. Usefulness of the genetic risk score to identify phenocopies in families with autosomal dominant hypercholesterolemia?

Author: Youmna Ghaleb, Sandy Elbitar, Catherine Boileau, Petra El Khoury, Mathilde Varret, Marianne Abifadel, and Jean-Pierre Rabès
Subjects: Phenocopy, Genetics, Biology, Genetic risk, Cardiology and Cardiovascular Medicine
Published: 2017
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43. Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs

Author: Sandy Elbitar, Marianne Abifadel, Youmna Ghaleb, Marie-Line Moussalli, Melody Chemaly, Catherine Boileau, Jean-Pierre Rabès, Mathilde Varret, and Petra El Khoury
Subjects: medicine.medical_specialty, Hypercholesterolemia, Familial hypercholesterolemia, Bioinformatics, chemistry.chemical_compound, Internal medicine, Medicine, Animals, Humans, Genetic Predisposition to Disease, Alirocumab, business.industry, Cholesterol, PCSK9, Anticholesteremic Agents, Serine Endopeptidases, Recovery of Function, medicine.disease, Proprotein convertase, Hypocholesterolemia, Evolocumab, Endocrinology, chemistry, LDL receptor, Mutation, Proprotein Convertases, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business
Abstract: A decade after our discovery of the involvement of proprotein convertase subtilisin/kexin type 9 (PCSK9) in cholesterol metabolism through the identification of the first mutations leading to hypercholesterolemia, PCSK9 has become one of the most promising targets in cholesterol and cardiovascular diseases. This challenging work in the genetics of hypercholesterolemia paved the way for a plethora of studies around the world allowing the characterization of PCSK9, its expression, its impact on reducing the abundance of LDL receptor, and the identification of loss-of-function mutations in hypocholesterolemia. We highlight the different steps of this adventure and review the published clinical trials especially those with the anti-PCSK9 antibodies evolocumab (AMG 145) and alirocumab (SAR236553/REGN727), which are in phase III trials. The promising results in lowering LDL cholesterol levels raise hope that the PCSK9 adventure will lead, after the large and long-term ongoing phase III studies evaluating efficacy and safety, to a new anticholesterol pharmacological class.
Published: 2014

44. Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects

Author: Bernard Chanu, Catherine Bonaïti-Pellié, Michel Krempf, Danielle Erlich, Catherine Boileau, Mathilde Varret, Martine Devillers, B. Saint-Jore, D. Mathé, Michel Farnier, Christiane Dachet, Bernard Jacotot, Claudine Junien, Patricia Blanchard, and Jean-Pierre Rabès
Subjects: Male, Candidate gene, Apolipoprotein B, Genetic Linkage, medicine.disease_cause, Hyperlipoproteinemia Type II, Genetic Heterogeneity, Genetic linkage, Genetics, medicine, Humans, Mathematical Computing, Gene, Triglycerides, Genetics (clinical), Apolipoproteins B, Mutation, biology, Genetic heterogeneity, Haplotype, Chromosome Mapping, nutritional and metabolic diseases, Cholesterol, LDL, Sequence Analysis, DNA, Pedigree, Haplotypes, Receptors, LDL, Chromosomes, Human, Pair 1, LDL receptor, biology.protein, Female, lipids (amino acids, peptides, and proteins), Lod Score, Microsatellite Repeats
Abstract: Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR/non APOB' families.
Published: 2000
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45. PCSK9, du gène à la protéine : un nouvel acteur dans l’homéostasie du cholestérol

Author: Marianne Abifadel, Catherine Boileau, Jean-Pierre Rabès, and Mathilde Varret
Subjects: Hypocholesterolemia, chemistry.chemical_compound, chemistry, Cholesterol, Mutation (genetic algorithm), medicine, General Medicine, Biology, medicine.disease, Molecular biology, Gene, General Biochemistry, Genetics and Molecular Biology
Published: 2006
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46. Familial ligand-defective apolipoprotein B-100: Simultaneous detection of the ARG3500→GLN and ARG3531→CYS mutations in a French population

Author: B. Saint-Jore, Guillaume Jondeau, Catherine Boileau, Mathilde Varret, Jean-Pierre Rabès, D. Erlich, Michel Krempf, Claudine Junien, and P Giraudet
Subjects: Proband, Genetics, education.field_of_study, Mutation, Apolipoprotein B, biology, Mutagenesis, Haplotype, Population, medicine.disease_cause, Molecular biology, Genotype, biology.protein, medicine, Allele, education, Genetics (clinical)
Abstract: Familial ligand-defective apolipoprotein B-100 (FDB) is an autosomal dominant disorder leading to plasma LDL cholesterol elevation and coronary artery disease (CAD). Two specific mutations in the APOB gene—R3500Q and R3531C—induce FDB. We report an original method to detect both mutations simultaneously, based upon PCR-mediated, site-directed mutagenesis and double restriction of a unique PCR product. With this method we have investigated the prevalence of these mutations in 1,040 French patients. The R3500Q mutation was found in five probands. Genotypes were determined for 10 APOB polymorphic markers and were consistent with the common European ancestral haplotype previously reported. The only exception was one FDB proband who did not harbor the 48 repeat allele of the 3′HVR. Additionally, the first two R3531C mutations were identified in French probands. Genotypes were consistent with a previously reported haplotype, suggesting that this is another mutation of European ancestry. Hum Mutat 10:160–163, 1997. © 1997 Wiley-Liss, Inc.
Published: 1997
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47. Exome sequencing in suspected monogenic dyslipidemias

Author: Sigrid W. Fouchier, Sekar Kathiresan, James G. Wilson, Marjorie Risman, Benjamin M. Neale, Catherine Boileau, Masa-aki Kawashiri, M. Mahdi Motazacker, Mathilde Varret, John J.P. Kastelein, Daniel J. Rader, G. Kees Hovingh, Clive R. Pullinger, Jorge F. Haller, Maurizio Averna, Stephen S. Rich, Angelo B. Cefalù, Isabelle Ruel, Jacques Genest, Nathan O. Stitziel, Rahul C. Deo, Namrata Gupta, Davide Noto, Deborah A. Nickerson, John P. Kane, Hiroshi Mabuchi, Jean-Pierre Rabès, Stacey Gabriel, Zuhier Awan, Mason W. Freeman, Deborah N. Farlow, Patrizia Tarugi, Atsushi Nohara, Mark J. Daly, Jay Shendure, Gina M. Peloso, Hayato Tada, Masakazu Yamagishi, Marianne Abifadel, Daniel B. Larach, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Vascular Medicine, Stitziel, N., Peloso, G., Abifadel, M., Cefalu, A., Fouchier, S., Motazacker, M., Tada, H., Larach, D., Awan, Z., Haller, J., Pullinger, C., Varret, M., Rabès, J., Noto, D., Tarugi, P., Kawashiri, M., Nohara, A., Yamagishi, M., Risman, M., Deo, R., Ruel, I., Shendure, J., Nickerson, D., Wilson, J., Rich, S., Gupta, N., Farlow, D., Neale, B., Daly, M., Kane, J., Freeman, M., Genest, J., Rader, D., Mabuchi, H., Kastelein, J., Hovingh, G., Averna, M., Gabriel, S., Boileau, C., and Kathiresan, S.
Subjects: Male, Settore MED/09 - Medicina Interna, Medical Biotechnology, DNA sequencing, exome, exome sequencing, genetics, human, lipids, mendelian genetics, Biology, Cardiorespiratory Medicine and Haematology, Novel gene, Gene mapping, Clinical Research, Genetics, 2.1 Biological and endogenous factors, Humans, genetics, Exome, human, Aetiology, Mendelian disorders, Genetics (clinical), Exome sequencing, Dyslipidemias, Inborn Errors, Human Genome, High-Throughput Nucleotide Sequencing, Atherosclerosis, Metabolism, Cardiovascular System & Hematology, lipids (amino acids, peptides, and proteins), Female, genetic, Cardiology and Cardiovascular Medicine, Metabolism, Inborn Errors
Abstract: Background— Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results— We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of common genetic variants known to influence lipid levels. In 9 families, we identified likely pathogenic variants in known lipid genes ( ABCA1 , APOB , APOE , LDLR, LIPA , and PCSK9 ); however, we were unable to identify obvious genetic etiologies in the remaining 32 families, despite follow-up analyses. We identified 3 factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. Conclusions— We identified the genetic basis of disease in 9 of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.
Published: 2013

48. Identification of a new mutation in the N-terminal region of the apolipoprotein B gene in familial hypercholesterolemia

Author: Sekar Kathiresan, Marianne Abifadel, Y. Ghaleb, Eric Bruckert, Mathilde Varret, N. Stitziel, S. Elbitar, Gina M. Peloso, Valérie Carreau, Jean-Pierre Rabès, P. El Khoury, and Catherine Boileau
Subjects: Genetics, Apolipoprotein B, biology, Terminal (electronics), New mutation, biology.protein, medicine, Identification (biology), Familial hypercholesterolemia, Cardiology and Cardiovascular Medicine, medicine.disease, Gene
Published: 2016
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49. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia

Author: Eric Bruckert, Michel Farnier, Isabel Beucler, Louise Wickham, Delphine Allard, Mathilde Varret, Khadija Ouguerram, Bernard Chanu, Annick Prat, Corinne Cruaud, Martine Devillers, Ludovic Villéger, Jean-Pierre Rabès, Jean Chambaz, Aurélie Derré, Gérald Luc, D. Erlich, Jean Weissenbach, Nabil G. Seidah, Michel Krempf, Suzanne Benjannet, Marianne Abifadel, Jean-Michel Lecerf, Claudine Junien, Philippe Moulin, and Catherine Boileau
Subjects: Genetics, PCSK9 Gene, Low-density lipoprotein receptor gene family, Apolipoprotein B, biology, Autosomal Recessive Hypercholesterolemia, PCSK9, LDL receptor, biology.protein, Kexin, lipids (amino acids, peptides, and proteins), Proprotein convertase
Abstract: Autosomal dominant hypercholesterolemia (ADH; OMIM144400), a risk factor for coronary heart disease, is characterized by an increase in low-density lipoprotein cholesterol levels that is associated with mutations in the genes LDLR (encoding low-density lipoprotein receptor) or APOB (encoding apolipoprotein B). We mapped a third locus associated with ADH, HCHOLA3 at 1p32, and now report two mutations in the gene PCSK9 (encoding proprotein convertase subtilisin/kexin type 9) that cause ADH. PCSK9 encodes NARC-1 (neural apoptosis regulated convertase), a newly identified human subtilase that is highly expressed in the liver and contributes to cholesterol homeostasis.
Published: 2003
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50. Genomic characterization of two deletions in the LDLR gene in Tunisian patients with familial hypercholesterolemia

Author: Jawher Mzid, Marianne Abifadel, Samir M'rabet, Catherine Boileau, Mohamed Najah, Jean-Pierre Rabès, Afef Slimani, Mathilde Varret, Imen Jguirim, Mohamed Naceur Slimane, and Awatef Jelassi
Subjects: Adult, Male, Tunisia, Adolescent, Genotype, Sequence analysis, Clinical Biochemistry, Alu element, Biology, medicine.disease_cause, Biochemistry, Polymerase Chain Reaction, Hyperlipoproteinemia Type II, PCSK9 Gene, medicine, Humans, Multiplex ligation-dependent probe amplification, Child, Gene, Genetics, Mutation, Biochemistry (medical), Serine Endopeptidases, Intron, Computational Biology, General Medicine, Middle Aged, Molecular biology, Receptors, LDL, LDL receptor, lipids (amino acids, peptides, and proteins), Female, Proprotein Convertases, Proprotein Convertase 9, Gene Deletion
Abstract: Autosomal Dominant Hypercholesterolemia (ADH) is due to defects in the LDL receptor gene (LDLR), the apolipoprotein B-100 gene (APOB) or the proprotein convertase subtilisin/kexin type 9 gene (PCSK9). The aim of this study was to identify and to characterize the ADH-causative mutations in two Tunisian families. Analysis of the LDLR gene was performed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA) and by long range PCR and sequencing. The PCSK9 gene was analysed by direct sequencing and the APOB gene was screened for the most common mutation: p.Arg3527Gln. In the LDLR gene, we found two large deletions and characterized their exact extent and breakpoint sequences. The first one is a deletion of 12,684 bp linking intron 1 to intron 5: g.11205052_11217736del12684. The second deletion spans 2364 bp from intron 4 to 6: g.11216885_11219249del2364. Sequence analysis of each deletion breakpoint indicates that intrachromatid non-allelic homologous recombination (NAHR) between Alu elements is involved. These two large rearrangements in the LDLR gene are the first to be described in the Tunisian population, increasing the spectrum of ADH-causative mutations.
Published: 2012

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