APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

International Journal of Molecular Sciences

Mathilde Di-Filippo¹  Oriane Marmontel¹  François Paillard²  Sybil Charrière³  Jean Ferrières⁴  Philippe Giral⁵  Valérie Carreau⁵  Antonio Gallo⁵  Eric Bruckert⁵  Cécile Yelnik⁶  Olivier Bluteau⁷  Alain Carrié⁷  Anne Philippi⁸  Catherine Boileau⁹  Marianne Abifadel⁹  Mathilde Varret⁹  Jean-Pierre Rabès⁹  Yara Abou Khalil⁹ 

[1] CarMen Laboratory, INSERM U1060, INRAE U1397, Université Lyon 1, F-69921 Oullins, France;Cardiovascular Prevention Centre, Centre Hospitalo-Universitaire, F-35033 Rennes, France;Department of Biochemistry and Molecular Biology, Hospices Civils de Lyon, F-69500 Bron, France;Department of Cardiology, Toulouse Rangueil University Hospital, UMR 1295 INSERM, F-31400 Toulouse, France;Department of Endocrinology and Prevention of Cardiovascular Disease, Institute of Cardio Metabolism and Nutrition (ICAN), La Pitié-Salpêtrière Hospital, AP-HP, F-75005 Paris, France;Département de Médecine Interne et Immunologie Clinique Centre de Référence des Maladies Auto-Immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO) CHU de Lille, F-59037 Lille, France;INSERM UMRS 1166, Faculty of Medicine Pitié-Salpêtrière, Sorbonne University, F-75005 Paris, France;Institut Cochin, Bâtiment Faculté Inserm U1016, Cnrs UMR8104, Université de Paris Faculté de Médecine, F-75014 Paris, France;Laboratory for Vascular Translational Science (LVTS), Paris Cité University and Sorbonne Paris Nord University, INSERM, F-75018 Paris, France;

关键词: hypercholesterolemia;    ADH;    FCHL;    apolipoprotein E;    APOE gene;    mutation;   

DOI  :  10.3390/ijms23105792

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown