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Clinical and genetic features of 2 patients with severe hypertriglyceridemia due to a mutation in GPIHBP1 gene
Nutrition, Metabolism & Cardiovascular Diseases 27 (2017) e4ee43 Available online at www.sciencedirect.com
Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd
Abstracts the Italian Society for the Study of Atherosclerosis (SISA) MODULAZIONE DELL'OMEOSTASI DEL COLESTEROLO DA PARTE DI PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) NEL MACROFAGO M.P. Adorni 1, I. Zanotti 1, E. Cipollari 1, E. Favari 1, F. Zimetti 1, A. Corsini 2, C. Ricci 2, F. Bernini 1, N. Ferri 3. 1 Dipartimento di degli studi di Parma, Parma, Italy; 2 Dipartimento Farmacia, Universita degli Studi di di Scienze Farmacologiche e Biomolecolari, Universita Milano, Milano, Italy; 3 Dipartimento di Scienze del Farmaco, Universita degli Studi di Padova, Padova, Italy E-mail address: [email protected] (M.P. Adorni).
una proteina Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) e appartenente alla famiglia delle proproteine convertasi espressa principalmente nel fegato, nell'intestino tenue, nel rene e nel sistema quella di regolare i nervoso centrale. La principale funzione di PCSK9 e livelli circolanti di LDL-C attraverso la degradazione del recettore per le LDL (LDLR) a livello epatico. PCSK9 contribuisce anche alla regolazione di altre funzioni cellulari in tessuti extraepatici come il macrofago del stato quello di valutare un lume vascolare. Lo scopo dello studio e possibile ruolo di PCSK9 nella modulazione del processo di efflusso di colesterolo mediato dalla proteina ATP-binding cassette transporter A1 stato valutato in (ABCA1) nel macrofago. L'efflusso del colesterolo e macrofagi peritoneali murini ottenuti da topi wild type (WT) e knockout per LDLR (LDLR-/-). Le cellule sono state stimolate per l'espressione del trasportatore ABCA1 mediante trattamento con agonisti dei recettori LXR/RXR ed esposte a PCSK9 ricombinante. L'efflusso ad apolipopro stato misurato attraverso tecniche radioisotopiche. L'espresteina AI e sione proteica e genica sono state valutate rispettivamente tramite Western blotting e real time PCR. PCSK9 inibisce del 55% (p<0.05) l'efflusso cellulare del colesterolo ABCA1-mediato indotto dagli agonisti LXR/RXR nei macrofagi WT ma non nei macrofagi LDLR-/-. Parallelamente PCSK9 inibisce l'espressione della proteina ABCA1 solo nei macrofagi WT. L'induzione dell'espressione genica di Abca1 mediata dagli agonisti LXR/RXR, viene inibita da PCSK9 ricombinante del 64% (p<0.001) nei macrofagi WT e, in misura minore, nei macrofagi LDLR-/(-35%, p<0.001). PCSK9 ha un effetto nullo o marginale sull'espressione genica rispettivamente di Abcg1 ed Sr-bi. PCSK9 ha un ruolo diretto sul processo di efflusso di colesterolo ABCA1-mediato nel macrofago attraverso l'inibizione dell'espressione del trasportatore ABCA1. Questo effetto necessita della presenza di LDLR probabilmente per mediare la sua internalizzazione. Questa azione di PCSK9 potrebbe essere rilevante nella patogenesi della malattia aterosclerotica promuovendo la formazione delle foam cells CLINICAL AND GENETIC FEATURES OF 2 PATIENTS WITH SEVERE HYPERTRIGLYCERIDEMIA DUE TO A MUTATION IN GPIHBP1 GENE G.I. Altieri, R. Spina, D. Noto, V. Ingrassia, V. Valenti, A. Giammanco, F. Fayer, G. Misiano, C. Scrimali, A. Ganci, C.M. Barbagallo, A.B. Cefalu', M.R. Averna. Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), University of Palermo, Palermo, Italy E-mail address: [email protected] (G.I. Altieri).
Background: Familial chylomicronemia is a recessive disorder that may be due to mutations in ipoprotein lipase (LPL) and in other proteins such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on
endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). Methods: We sequenced the familial chylomicronemia candidate genes in one adult patient presenting long-standing severe hypertriglyceridemia. Results: The proband had plasma triglyceride >10 mmol/L but no mutations in the LPL gene. The sequence of the other candidate genes by Next Generation Sequencing (NGS) showed that the patient was homozygous for a frameshift mutation (c.413_429delTCCCACCCTGGCAAAGC p.Val138fs) in GPIHBP1 that is expected to result in a truncated protein devoid of function; this mutation affecs the Ly6 domain of GPIHBP1 that is required to maintain the structure of GPIHBP1 protein. The mutation has been previously described in a 5-week-old Hispanic girl with severe HTG in which whole exome sequencing revealed this mutation for the first time in compound heterozygosity. The proband's sister was carrier of the same mutation in homozygosity and she also showed severe hypertriglyceridemia. Conclusions: We identified a frameshift mutation in GPIHBP1 gene in a family affected by severe hypertrigliceridemia by a NGS approach. PRELIMINARY CLINICAL EXPERIENCE OF PCSK9 INHIBITORS IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA. CONSIDERATIONS ON THEIR USE IN PATI-ENTS ON LIPOPROTEIN APHERESIS TREATMENT AND IN STATINS INTOLERANT PATIENTS A. Altomari 1, V. Sanga 1, G. Ceradini 1, A. Fabris 2, A. Lupo 2, E. Bonora 1, M. Dauriz 1, M.G. Zenti 1. 1 Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy; 2 Section of Nephrology, Department of Medicine, University Hospital of Verona, Verona, Italy E-mail address: [email protected] (A. Altomari).
The introduction of monoclonal antibodies anti-PCSK9 as a treatment option in patients with Heterozygous Familial Hypercholesterolemia (HeFH) represents a recent advancement in the pharmacological toolbox currently available to reach the recommended individual LDLcholesterol (LDL-C) target. Methods: We evaluated 12 HeFH outpatients carrying a mutation on LDLR gene (6M/6F), average age 57.3 y (range 36-74), BMI 25.8±3.3 kg/ m2, and with personal history of cardiovascular disease (CVD), under treatment with PCSK9 inhibitors (PCSK9-i). We indentified two subgroup of patients, according to the therapeutic scheme applied: Group-A comprised of 9 patients in which PCSK9-i was started as add-on treatment to the maximum-tolerated-dose of statins+ezetimibe combination therapy; Group-B, comprising 3 patients with complete intolerance to the statin and ezetimibe therapy, in which the PCSK9-i have been applied as monotherapy. Evolocumab (140 mg sc, twice a month) was administred to 6 patients (3M/3F; 4 from Group-A; 2 from Group-B). Alirocumab was administred to 6 patients (3M/3F): 75 mg twice a month in 4 patients from Group-A; 150 mg twice a month in 1 patient from Group-A and 1 from Group-B. The ongoing lipoprotein-apheresis (LA) treatment in 5 Group- A patients was discontinued upon the initiation of the therapy with evoculamb (4) or alirocumab (1). Plasma levels of totalcholesterol, LDL-C, HDL-C, triglycerides, fasting plasma glucose, liver transaminases, creatine-kinase and creatinine were measured at the beginning of PCSK9-i therapy and after 1-3 and 6 months. Results: Basal LDL-C levels in Group-A patients were (mean±SD) 140±126 mg/dl, and after 1-3 and 6 months of treatment with
Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd
Abstracts the Italian Society for the Study of Atherosclerosis (SISA) MODULAZIONE DELL'OMEOSTASI DEL COLESTEROLO DA PARTE DI PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) NEL MACROFAGO M.P. Adorni 1, I. Zanotti 1, E. Cipollari 1, E. Favari 1, F. Zimetti 1, A. Corsini 2, C. Ricci 2, F. Bernini 1, N. Ferri 3. 1 Dipartimento di degli studi di Parma, Parma, Italy; 2 Dipartimento Farmacia, Universita degli Studi di di Scienze Farmacologiche e Biomolecolari, Universita Milano, Milano, Italy; 3 Dipartimento di Scienze del Farmaco, Universita degli Studi di Padova, Padova, Italy E-mail address: [email protected] (M.P. Adorni).
una proteina Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) e appartenente alla famiglia delle proproteine convertasi espressa principalmente nel fegato, nell'intestino tenue, nel rene e nel sistema quella di regolare i nervoso centrale. La principale funzione di PCSK9 e livelli circolanti di LDL-C attraverso la degradazione del recettore per le LDL (LDLR) a livello epatico. PCSK9 contribuisce anche alla regolazione di altre funzioni cellulari in tessuti extraepatici come il macrofago del stato quello di valutare un lume vascolare. Lo scopo dello studio e possibile ruolo di PCSK9 nella modulazione del processo di efflusso di colesterolo mediato dalla proteina ATP-binding cassette transporter A1 stato valutato in (ABCA1) nel macrofago. L'efflusso del colesterolo e macrofagi peritoneali murini ottenuti da topi wild type (WT) e knockout per LDLR (LDLR-/-). Le cellule sono state stimolate per l'espressione del trasportatore ABCA1 mediante trattamento con agonisti dei recettori LXR/RXR ed esposte a PCSK9 ricombinante. L'efflusso ad apolipopro stato misurato attraverso tecniche radioisotopiche. L'espresteina AI e sione proteica e genica sono state valutate rispettivamente tramite Western blotting e real time PCR. PCSK9 inibisce del 55% (p<0.05) l'efflusso cellulare del colesterolo ABCA1-mediato indotto dagli agonisti LXR/RXR nei macrofagi WT ma non nei macrofagi LDLR-/-. Parallelamente PCSK9 inibisce l'espressione della proteina ABCA1 solo nei macrofagi WT. L'induzione dell'espressione genica di Abca1 mediata dagli agonisti LXR/RXR, viene inibita da PCSK9 ricombinante del 64% (p<0.001) nei macrofagi WT e, in misura minore, nei macrofagi LDLR-/(-35%, p<0.001). PCSK9 ha un effetto nullo o marginale sull'espressione genica rispettivamente di Abcg1 ed Sr-bi. PCSK9 ha un ruolo diretto sul processo di efflusso di colesterolo ABCA1-mediato nel macrofago attraverso l'inibizione dell'espressione del trasportatore ABCA1. Questo effetto necessita della presenza di LDLR probabilmente per mediare la sua internalizzazione. Questa azione di PCSK9 potrebbe essere rilevante nella patogenesi della malattia aterosclerotica promuovendo la formazione delle foam cells CLINICAL AND GENETIC FEATURES OF 2 PATIENTS WITH SEVERE HYPERTRIGLYCERIDEMIA DUE TO A MUTATION IN GPIHBP1 GENE G.I. Altieri, R. Spina, D. Noto, V. Ingrassia, V. Valenti, A. Giammanco, F. Fayer, G. Misiano, C. Scrimali, A. Ganci, C.M. Barbagallo, A.B. Cefalu', M.R. Averna. Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), University of Palermo, Palermo, Italy E-mail address: [email protected] (G.I. Altieri).
Background: Familial chylomicronemia is a recessive disorder that may be due to mutations in ipoprotein lipase (LPL) and in other proteins such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on
endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). Methods: We sequenced the familial chylomicronemia candidate genes in one adult patient presenting long-standing severe hypertriglyceridemia. Results: The proband had plasma triglyceride >10 mmol/L but no mutations in the LPL gene. The sequence of the other candidate genes by Next Generation Sequencing (NGS) showed that the patient was homozygous for a frameshift mutation (c.413_429delTCCCACCCTGGCAAAGC p.Val138fs) in GPIHBP1 that is expected to result in a truncated protein devoid of function; this mutation affecs the Ly6 domain of GPIHBP1 that is required to maintain the structure of GPIHBP1 protein. The mutation has been previously described in a 5-week-old Hispanic girl with severe HTG in which whole exome sequencing revealed this mutation for the first time in compound heterozygosity. The proband's sister was carrier of the same mutation in homozygosity and she also showed severe hypertriglyceridemia. Conclusions: We identified a frameshift mutation in GPIHBP1 gene in a family affected by severe hypertrigliceridemia by a NGS approach. PRELIMINARY CLINICAL EXPERIENCE OF PCSK9 INHIBITORS IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA. CONSIDERATIONS ON THEIR USE IN PATI-ENTS ON LIPOPROTEIN APHERESIS TREATMENT AND IN STATINS INTOLERANT PATIENTS A. Altomari 1, V. Sanga 1, G. Ceradini 1, A. Fabris 2, A. Lupo 2, E. Bonora 1, M. Dauriz 1, M.G. Zenti 1. 1 Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy; 2 Section of Nephrology, Department of Medicine, University Hospital of Verona, Verona, Italy E-mail address: [email protected] (A. Altomari).
The introduction of monoclonal antibodies anti-PCSK9 as a treatment option in patients with Heterozygous Familial Hypercholesterolemia (HeFH) represents a recent advancement in the pharmacological toolbox currently available to reach the recommended individual LDLcholesterol (LDL-C) target. Methods: We evaluated 12 HeFH outpatients carrying a mutation on LDLR gene (6M/6F), average age 57.3 y (range 36-74), BMI 25.8±3.3 kg/ m2, and with personal history of cardiovascular disease (CVD), under treatment with PCSK9 inhibitors (PCSK9-i). We indentified two subgroup of patients, according to the therapeutic scheme applied: Group-A comprised of 9 patients in which PCSK9-i was started as add-on treatment to the maximum-tolerated-dose of statins+ezetimibe combination therapy; Group-B, comprising 3 patients with complete intolerance to the statin and ezetimibe therapy, in which the PCSK9-i have been applied as monotherapy. Evolocumab (140 mg sc, twice a month) was administred to 6 patients (3M/3F; 4 from Group-A; 2 from Group-B). Alirocumab was administred to 6 patients (3M/3F): 75 mg twice a month in 4 patients from Group-A; 150 mg twice a month in 1 patient from Group-A and 1 from Group-B. The ongoing lipoprotein-apheresis (LA) treatment in 5 Group- A patients was discontinued upon the initiation of the therapy with evoculamb (4) or alirocumab (1). Plasma levels of totalcholesterol, LDL-C, HDL-C, triglycerides, fasting plasma glucose, liver transaminases, creatine-kinase and creatinine were measured at the beginning of PCSK9-i therapy and after 1-3 and 6 months. Results: Basal LDL-C levels in Group-A patients were (mean±SD) 140±126 mg/dl, and after 1-3 and 6 months of treatment with