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

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.

[1]  D. Rader,et al.  Angptl3 Deficiency Is Associated With Increased Insulin Sensitivity, Lipoprotein Lipase Activity, and Decreased Serum Free Fatty Acids , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[2]  G. Labbadia,et al.  Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. , 2012, The Journal of clinical endocrinology and metabolism.

[3]  J. Kastelein,et al.  Antisense oligonucleotides for the treatment of dyslipidaemia. , 2012, European heart journal.

[4]  Sander Kersten,et al.  Regulation of triglyceride metabolism by Angiopoietin-like proteins. , 2012, Biochimica et biophysica acta.

[5]  F. Blanco-Vaca,et al.  Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation. , 2012, Clinica chimica acta; international journal of clinical chemistry.

[6]  S. Kathiresan,et al.  Prevalence of ANGPTL3 and APOB Gene Mutations in Subjects With Combined Hypolipidemia , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[7]  G. Franceschini,et al.  Characterization of Three Kindreds With Familial Combined Hypolipidemia Caused by Loss-of-Function Mutations of ANGPTL3 , 2012, Circulation. Cardiovascular genetics.

[8]  I. Gouni-Berthold,et al.  Antisense oligonucleotides for the treatment of dyslipidemia. , 2011, Current pharmaceutical design.

[9]  P. Tarugi,et al.  Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum. , 2011, Advances in clinical chemistry.

[10]  Jonathan C. Cohen,et al.  Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. , 2010, The New England journal of medicine.

[11]  G. Bedogni,et al.  A simple index of lipid overaccumulation is a good marker of liver steatosis , 2010, BMC gastroenterology.

[12]  T. Miida,et al.  Impacts of angiopoietin-like proteins on lipoprotein metabolism and cardiovascular events , 2010, Current opinion in lipidology.

[13]  Eric Boerwinkle,et al.  Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. , 2008, The Journal of clinical investigation.

[14]  G. Marchesini,et al.  Obesity-associated liver disease. , 2008, The Journal of clinical endocrinology and metabolism.

[15]  Martin Adiels,et al.  Overproduction of Very Low–Density Lipoproteins Is the Hallmark of the Dyslipidemia in the Metabolic Syndrome , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[16]  Andrea Laghi,et al.  MRI and ultrasound for hepatic fat quantification:relationships to clinical and metabolic characteristics of pediatric nonalcoholic fatty liver disease , 2007, Acta paediatrica.

[17]  M. Matsuda,et al.  Angiopoietin-Like Protein3 Regulates Plasma HDL Cholesterol Through Suppression of Endothelial Lipase , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[18]  Cai Li.  Genetics and regulation of angiopoietin-like proteins 3 and 4 , 2006, Current opinion in lipidology.

[19]  J. Kastelein,et al.  Hepatic and Cardiovascular Consequences of Familial Hypobetalipoproteinemia , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[20]  G. Schonfeld,et al.  Familial hypobetalipoproteinemia: genetics and metabolism , 2005, Cellular and Molecular Life Sciences.

[21]  Alexander Pertsemlidis,et al.  Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 , 2005, Nature Genetics.

[22]  F. V. van Bockxmeer,et al.  Monogenic Hypocholesterolaemic Lipid Disorders and Apolipoprotein B Metabolism , 2005, Critical reviews in clinical laboratory sciences.

[23]  E. Boerwinkle,et al.  Genetics of the quantitative Lp(a) lipoprotein trait , 1989, Human Genetics.

[24]  G. Utermann,et al.  Genetics of the quantitative Lp(a) lipoprotein trait , 2004, Human Genetics.

[25]  Kenichi Yoshida,et al.  Protein Region Important for Regulation of Lipid Metabolism in Angiopoietin-like 3 (ANGPTL3) , 2003, Journal of Biological Chemistry.

[26]  M. Shimamura,et al.  A decreased expression of angiopoietin-like 3 is protective against atherosclerosis in apoE-deficient mice Published, JLR Papers in Press, April 2, 2003. DOI 10.1194/jlr.M300031-JLR200 , 2003, Journal of Lipid Research.

[27]  D. Yablonskiy,et al.  Fatty liver in familial hypobetalipoproteinemia: triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. , 2003, Journal of lipid research.

[28]  M. Matsuda,et al.  Angiopoietin-like protein 3, a hepatic secretory factor, activates lipolysis in adipocytes. , 2003, Biochemical and biophysical research communications.

[29]  Kenichi Yoshida,et al.  ANGPTL3 Decreases Very Low Density Lipoprotein Triglyceride Clearance by Inhibition of Lipoprotein Lipase* , 2002, The Journal of Biological Chemistry.

[30]  T. Fujiwara,et al.  Angptl3 regulates lipid metabolism in mice , 2002, Nature Genetics.

[31]  G. Schonfeld,et al.  In vivo metabolism of ApoB, ApoA-I, and VLDL triglycerides in a form of hypobetalipoproteinemia not linked to the ApoB gene. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[32]  G. Brandi,et al.  Prevalence of and Risk Factors for Hepatic Steatosis in Northern Italy , 2000, Annals of Internal Medicine.

[33]  P. Kwok,et al.  Known mutations of apoB account for only a small minority of hypobetalipoproteinemia. , 1999, Journal of Lipid Research.

[34]  W. Gross,et al.  Bestimmung von Lipoprotein(a): Vergleich eines neuen latexverstärkten immunoturbidimetrischen Assay mit einem immunoradiometrischen Assay , 1996 .

[35]  D. Noto,et al.  Familial hypobetalipoproteinemia is not associated with low levels of lipoprotein(a). , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[36]  A. Joseph,et al.  Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. , 1991, Clinical radiology.

[37]  D. T. Vernier,et al.  Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. , 1990, Journal of lipid research.

[38]  G. Utermann,et al.  The mysteries of lipoprotein(a). , 1989, Science.