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. 2013 Dec;54(12):3481-90.
doi: 10.1194/jlr.P039875. Epub 2013 Sep 20.

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

Ilenia Minicocci  1 , Sara Santini, Vito Cantisani, Nathan Stitziel, Sekar Kathiresan, Juan Antonio Arroyo, Gertrudis Martí, Livia Pisciotta, Davide Noto, Angelo B Cefalù, Marianna Maranghi, Giancarlo Labbadia, Giovanni Pigna, Fabio Pannozzo, Fabrizio Ceci, Ester Ciociola, Stefano Bertolini, Sebastiano Calandra, Patrizia Tarugi, Maurizio Averna, Marcello Arca
Affiliations

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

Ilenia Minicocci et al. J Lipid Res. 2013 Dec.

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.

Keywords: ANGPTL3 mutations; angiopoietin-like 3; cardiovascular disease; diabetes mellitus; fatty liver.

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Figures

Fig. 1.
Fig. 1.
Grade of liver steatosis in FHBL2 subjects carrying the ANGPTL3 p.S17* mutation and noncarrier controls.
Fig. 2.
Fig. 2.
Adjusted plasma lipid residuals, according to the number of mutant ANGPTL3 alleles. Shown are the levels of TC- (A), HDL-C- (B), TG- (C), LDL-C- (D), apo-B- (E), and apoAI- (F) residuals according to the ANGPTL3 genotype. The box plots give the median levels (middle horizontal line in each box), the interquartile ranges (delineated by the top and bottom of each box), and outliers falling below the 5th percentile or above the 95th percentile (points below or above the vertical lines, respectively).
Fig. 3.
Fig. 3.
Time-trend changes of plasma lipids in ANGPTL3 mutations carriers and noncarriers. LDL-C (A), TG (B), HDL-C (C), and apoB (D). *P < 0.05; **P < 0.01; ***P < 0.001 for comparison between 2007 and 2011 examinations.
Fig. 4.
Fig. 4.
Serum ANGPTL3 levels according to carriers of the different ANGPTL3 gene variants. Shown are the mean plasma levels of ANGPTL3 according to the genotype. The box plots give the median levels (middle horizontal line in each box), the interquartile ranges (delineated by the top and bottom of each box), and outliers falling below the 5th percentile or above the 95th percentile (points below or above the vertical lines, respectively
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References

    1. Schonfeld G., Lin X., Yue P. 2005. Familial hypobetalipoproteinemia: genetics and metabolism. Cell. Mol. Life Sci. 62: 1372–1378 - PMC - PubMed
    1. Hooper A. J., van Bockxmeer F. M., Burnett J. R. 2005. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Crit. Rev. Clin. Lab. Sci. 42: 515–545 - PubMed
    1. Wu J., Kim J., Li Q., Kwok P. Y., Cole T. G., Cefalu B., Averna M., Schonfeld G. 1999. Known mutations of apoB account for only a small minority of hypobetalipoproteinemia. J. Lipid Res. 40: 955–959 - PubMed
    1. Schonfeld G., Patterson B. W., Yablonskiy D. A., Tanoli T. S., Averna M., Elias N., Yue P., Ackerman J. 2003. Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. J. Lipid Res. 44: 470–478 - PubMed
    1. Cohen J., Pertsemlidis A., Kotowski I. K., Graham R., Garcia C. K., Hobbs H. H. 2005. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37: 161–165 - PubMed

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