Contributors: 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 Saint-Joseph de Beyrouth (USJ); 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); Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)); Hôpital Louis Pradel CHU - HCL; Hospices Civils de Lyon (HCL); 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); Physiopathologie et épidémiologie cérébro-cardiovasculaire Dijon (PEC2); Université de Bourgogne (UB)-Université Bourgogne Franche-Comté COMUE (UBFC); Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE); 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 CHU Lille (CHRU Lille); Centre Hospitalier Régional Universitaire CHU 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); Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); Centre d'Epidémiologie et de Recherche en santé des POPulations (CERPOP); 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); Service Cardiologie CHU Toulouse; Pôle Cardiovasculaire et Métabolique CHU Toulouse; Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse); Réseau International des Instituts Pasteur (RIIP); McGill University Health Center Montreal (MUHC); Institut de Recherches Cliniques de Montréal (IRCM); Université de Montréal (UdeM); McGill University = Université McGill Montréal, Canada; University Hospital Bonn; Centre National de Recherche en Génomique Humaine (CNRGH); Institut de Biologie François JACOB (JACOB); Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA); Laboratory of Excellence GENMED Paris (Medical Genomics); Centre d'Etude du Polymorphisme Humain (CEPH); Institut Universitaire d'Hématologie (IUH); Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset-Université Paris Cité (UPCité); 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); PCSK9013; 13CVD03; ANR-10-LABX-0013; National Institutes of Health, NIH: BB-033-00065, R01 HL107816; Broad Institute; International Atherosclerosis Society, IAS; Canadian Institutes of Health Research, IRSC: 2017–2022; Fonds de Recherche du Québec - Santé, FRQS; 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; This work was supported by grants from the Leducq Foundation (FLQ # 13CVD03), the Laboratory of Excellence GENMED (Medical Genomics) grant no. ANR-10-LABX-0013 managed by the National Research Agency (ANR), part of the Investment for the Future program, and 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). Youmna Ghaleb is supported by a grant from the Lefoulon-Delalande Foundation and the International Atherosclerosis Society (IAS). Yara Azar and Yara Abou-Khalil are supported by grants from the Lebanese National Council for Scientific Research (CNRS-L) and the Council of Research of Saint-Joseph University of Beirut, Lebanon; Yara Azar is supported by a grant from AMGEN funding (PCSK9013). Yara Abou-Khalil is supported by a grant from Minist?re de l?Education Nationale et de la Technologie (France) and a grant from Nouvelle Soci?t? Francophone de l?Ath?roscl?rose (France). Genevi?ve Bernard received a Research Scholar Junior 1 award from the Fonds de Recherche du Qu?bec?Sant? (FRQS) (2012?2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017?2022). Acknowledgments: We thank all family members and the proband cohort for participating in the study. We thank Sekar Kathiresan, Gina Peloso and Nathan Stitziel (Broad Institute of MIT, Boston, MA, USA) for their help in the exome sequencing experiments. Sekar Kathiresan was supported by NIH R01 HL107816. We acknowledge the use of the bioresources of the Necker DNA Biobank (BB-033-00065). We thank Silvia Friedrichs for the technical assistance in sterol and bile acid analyses by GC-MS.; Funding: This work was supported by grants from the Leducq Foundation (FLQ # 13CVD03), the Laboratory of Excellence GENMED (Medical Genomics) grant no. ANR-10-LABX-0013 managed by the National Research Agency (ANR), part of the Investment for the Future program, and 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). Youmna Ghaleb is supported by a grant from the Lefoulon-Delalande Foundation and the International Atherosclerosis Society (IAS). Yara Azar and Yara Abou-Khalil are supported by grants from the Lebanese National Council for Scientific Research (CNRS-L) and the Council of Research of Saint-Joseph University of Beirut, Lebanon; Yara Azar is supported by a grant from AMGEN funding (PCSK9013). Yara Abou-Khalil is supported by a grant from Ministère de l’Education Nationale et de la Technologie (France) and a grant from Nouvelle Société Francophone de l’Athérosclérose (France). Geneviève Bernard received a Research Scholar Junior 1 award from the Fonds de Recherche du Québec—Santé (FRQS) (2012–2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017–2022).; Acknowledgments: We thank all family members and the proband cohort for participating in the study. We thank Sekar Kathiresan, Gina Peloso and Nathan Stitziel (Broad Institute of MIT, Boston, MA, USA) for their help in the exome sequencing experiments. Sekar Kathiresan was supported by NIH R01 HL107816. We acknowledge the use of the bioresources of the Necker DNA Biobank (BB-033-00065). We thank Silvia Friedrichs for the technical assistance in sterol and bile acid analyses by GC-MS.; ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016)
نبذة مختصرة : International audience ; 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.
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