Petra El Khoury1, Philippe Couvert2, Sandy Elbitar1, Youmna Ghaleb1, Yara Abou-Khalil1, Yara Azar3, Carine Ayoub3, Alexandre Superville4, Maryse Guérin4, Jean-Pierre Rabès5, Mathilde Varret6, Catherine Boileau7, Selim Jambart8, Philippe Giral9, Alain Carrié10, Wilfried Le Goff4, Marianne Abifadel11. 1. Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie- Santé, Saint Joseph University, Beirut, Lebanon; INSERM LVTS U1148, Hôpital Bichat-Claude Bernard, Paris, France. 2. Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Pôle de Biologie Médicale et Pathologie, Centre de Génétique Moléculaire et Chromosomique, Paris, France; Sorbonne Université, Inserm, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S1166, Paris, France. 3. Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie- Santé, Saint Joseph University, Beirut, Lebanon. 4. Sorbonne Université, Inserm, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S1166, Paris, France. 5. Assistance Publique-Hôpitaux de Paris, HUPIFO, hôpital Ambroise-Paré, Laboratoire de Biochimie et de Génétique Moléculaire, Boulogne-Billancourt et UVSQ, UFR des Sciences de la Santé Simone Veil, Montigny-le-Bretonneux, France. 6. INSERM LVTS U1148, Hôpital Bichat-Claude Bernard, Paris, France. 7. INSERM LVTS U1148, Hôpital Bichat-Claude Bernard, Paris, France; Paris Diderot University, Paris, France; Service de Génétique, Hôpital Bichat-Claude Bernard, Paris, France. 8. Saint Joseph University of Beirut Faculty of Medicine, Hôtel Dieu Hospital, Beirut, Lebanon. 9. Sorbonne Université, Inserm, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S1166, Paris, France; Department of Endocrinology-Metabolism, AP-HP, Hôpital de la Pitié, Paris, France. 10. Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Pôle de Biologie Médicale et Pathologie, Centre de Génétique Moléculaire et Chromosomique, Paris, France. 11. Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie- Santé, Saint Joseph University, Beirut, Lebanon; INSERM LVTS U1148, Hôpital Bichat-Claude Bernard, Paris, France. Electronic address: marianne.abi-fadel@inserm.fr.
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.
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.