Ilenia Minicocci1, Cristina Prisco1, Anna Montali1, Alessia Di Costanzo1, Fabrizio Ceci2, Giovanni Pigna1, Marcello Arca3. 1. Department of Internal Medicine and Allied Sciences, Unit of Atherosclerosis and Lipid Disorders, Sapienza University of Rome, Rome, Italy. 2. Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy. 3. Department of Internal Medicine and Allied Sciences, Unit of Atherosclerosis and Lipid Disorders, Sapienza University of Rome, Rome, Italy. Electronic address: marcelloarca@libero.it.
Abstract
BACKGROUND: Defective low-density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) alleles have been implicated in familial combined hyperlipidemia (FCHL). However, their contribution might have been influenced by diagnostic criteria. This study was aimed to reassess the frequency of rare and common variants in LDLR and LPL in FCHL individuals classified with stringent criteria. METHODS: LDLR and LPL were resequenced in 208 FHCL and 171 controls. Variants were classified as loss- (LOF) or gain-of-function (GOF) based upon in silico prediction, familial segregation and available functional data. RESULTS: Eight LOF variants were detected in LDLR, 6 of which were missense and 2 were predicted to disrupt normal splicing; all were present at heterozygous state. They were found in 10 FCHL but not in controls, thus indicating that 4.8% of FCHL individuals should be reclassified as FH. LDL-C (positive) and BMI (negative) were the strongest predictors of LDLR mutations with LDL-C 181 mg/dl being the best threshold for diagnosing the presence of dysfunctional LDLR alleles. The cumulative prevalence of definite LPL defective alleles (1 rare and 2 common heterozygous missense variants) was comparable between FCHL and controls (10.1% vs. 10.5%). Conversely, the LPL GOF variant p.Ser474* showed a lower frequency in FCHL than in controls (13.5% vs. 24.0%, p = 0.008). Overall, LOF LPL variants did not show a TG-modulating effect. CONCLUSIONS: Our findings indicate that, in well characterized FCHL individuals, variants in LDLR and LPL provide a small contribution to this dyslipidemia, thus limiting the need for such genetic testing.
BACKGROUND: Defective low-density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) alleles have been implicated in familial combined hyperlipidemia (FCHL). However, their contribution might have been influenced by diagnostic criteria. This study was aimed to reassess the frequency of rare and common variants in LDLR and LPL in FCHL individuals classified with stringent criteria. METHODS:LDLR and LPL were resequenced in 208 FHCL and 171 controls. Variants were classified as loss- (LOF) or gain-of-function (GOF) based upon in silico prediction, familial segregation and available functional data. RESULTS: Eight LOF variants were detected in LDLR, 6 of which were missense and 2 were predicted to disrupt normal splicing; all were present at heterozygous state. They were found in 10 FCHL but not in controls, thus indicating that 4.8% of FCHL individuals should be reclassified as FH. LDL-C (positive) and BMI (negative) were the strongest predictors of LDLR mutations with LDL-C 181 mg/dl being the best threshold for diagnosing the presence of dysfunctional LDLR alleles. The cumulative prevalence of definite LPL defective alleles (1 rare and 2 common heterozygous missense variants) was comparable between FCHL and controls (10.1% vs. 10.5%). Conversely, the LPL GOF variant p.Ser474* showed a lower frequency in FCHL than in controls (13.5% vs. 24.0%, p = 0.008). Overall, LOF LPL variants did not show a TG-modulating effect. CONCLUSIONS: Our findings indicate that, in well characterized FCHL individuals, variants in LDLR and LPL provide a small contribution to this dyslipidemia, thus limiting the need for such genetic testing.
Authors: Ilenia Minicocci; Anna Tikka; Eleonora Poggiogalle; Jari Metso; Anna Montali; Fabrizio Ceci; Giancarlo Labbadia; Mario Fontana; Alessia Di Costanzo; Marianna Maranghi; Aldo Rosano; Christian Ehnholm; Lorenzo Maria Donini; Matti Jauhiainen; Marcello Arca Journal: J Lipid Res Date: 2016-04-03 Impact factor: 5.922
Authors: A M Bea; E Franco-Marín; V Marco-Benedí; E Jarauta; I Gracia-Rubio; A Cenarro; F Civeira; I Lamiquiz-Moneo Journal: Sci Rep Date: 2021-03-26 Impact factor: 4.379