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Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis.

ABSTRACT: Angiopoietin-like 3 (ANGPTL3) regulates lipoprotein metabolism by modulating extracellular lipases. Loss-of function mutations in ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). The mode of inheritance and hepatic and vascular consequences of FHBL2 have not been fully elucidated. To get further insights on these aspects, we reevaluated the clinical and the biochemical characteristics of all reported cases of FHBL2. One hundred fifteen FHBL2 individuals carrying 13 different mutations in the ANGPTL3 gene (14 homozygotes, 8 compound heterozygotes, and 93 heterozygotes) and 402 controls were considered. Carriers of two mutant alleles had undetectable plasma levels of ANGPTL3 protein, whereas heterozygotes showed a reduction ranging from 34% to 88%, according to genotype. Compared with controls, homozygotes as well as heterozygotes showed a significant reduction of all plasma lipoproteins, while no difference in lipoprotein(a) [Lp(a)] levels was detected between groups. The prevalence of fatty liver was not different in FHBL2 subjects compared with controls. Notably, diabetes mellitus and cardiovascular disease were absent among homozygotes. FHBL2 trait is inherited in a codominant manner, and the lipid-lowering effect of two ANGPTL3 mutant alleles was more than four times larger than that of one mutant allele. No changes in Lp(a) were detected in FHBL2. Furthermore, our analysis confirmed that FHBL2 is not associated with adverse clinical sequelae. The possibility that FHBL2 confers lower risk of diabetes and cardiovascular disease warrants more detailed investigation.

SUBMITTER: Minicocci I

PROVIDER: S-EPMC3826694 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis.

Minicocci Ilenia I Santini Sara S Cantisani Vito V Stitziel Nathan N Kathiresan Sekar S Arroyo Juan Antonio JA Martí Gertrudis G Pisciotta Livia L Noto Davide D Cefalù Angelo B AB Maranghi Marianna M Labbadia Giancarlo G Pigna Giovanni G Pannozzo Fabio F Ceci Fabrizio F Ciociola Ester E Bertolini Stefano S Calandra Sebastiano S Tarugi Patrizia P Averna Maurizio M Arca Marcello M

Journal of lipid research 20130920 12

Angiopoietin-like 3 (ANGPTL3) regulates lipoprotein metabolism by modulating extracellular lipases. Loss-of function mutations in ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). The mode of inheritance and hepatic and vascular consequences of FHBL2 have not been fully elucidated. To get further insights on these aspects, we reevaluated the clinical and the biochemical characteristics of all reported cases of FHBL2. One hundred fifteen FHBL2 individuals carrying 13 different mutations ...[more]

PMID: 24058201

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Project description:ContextFamilial combined hypolipidemia causes a global reduction of plasma lipoproteins. Its clinical correlates and metabolic implications have not been well defined.ObjectiveThe objective of the study was to investigate the genetic, clinical, and metabolic characteristics of a cohort of subjects with familial combined hypolipidemia.DesignThe design of the study included candidate gene screening and the comparison of the clinical and metabolic characteristics between carrier and noncarrier individuals.SettingThe study was conducted in a general community.SubjectsParticipants in the study included individuals belonging to nine families with familial combined hypolipidemia identified in a small town (Campodimele) as well as from other 352 subjects living in the same community.Main outcomes measuresSerum concentrations of lipoproteins, Angiopoietin-like 3 (Angptl3) proteins, and noncholesterol sterols were measured.ResultsThe ANGPTL3 S17X mutation was found in all probands, 20 affected family members, and 32 individuals of the community. Two additional frame shift mutations, FsE96del and FsS122, were also identified in two hypocholesterolemic individuals. Homozygotes for the ANGPTL3 S17X mutation had no circulating Angptl3 and a marked reduction of all plasma lipids (P < 0.001). Heterozygotes had 42% reduction in Angptl3 level compared with noncarriers (P < 0.0001) but a significant reduction of only total cholesterol and high-density lipoprotein cholesterol. No differences were observed in the plasma noncholesterol sterols between carriers and noncarriers. No association between familial combined hypolipidemia and the risk of hepatic or cardiovascular diseases were detected.ConclusionsFamilial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B- and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. Familial combined hypolipidemia does not perturb whole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.

Dataset Information

Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis.

Publications

Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis.

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