Mutations in the ANGPTL3 Gene and Familial Combined Hypolipidemia: A Clinical and Biochemical Characterization

Context: Familial combined hypolipidemia causes a global reduction of plasma lipoproteins. Its clinical correlates and metabolic implications have not been well defined. Objective: The objective of the study was to investigate the genetic, clinical, and metabolic characteristics of a cohort of subjects with familial combined hypolipidemia. Design: The design of the study included candidate gene screening and the comparison of the clinical and metabolic characteristics between carrier and noncarrier individuals. Setting: The study was conducted in a general community. Subjects: Participants 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 Measures: Serum concentrations of lipoproteins, Angiopoietin-like 3 (Angptl3) proteins, and noncholesterol sterols were measured. Results: The 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. Conclusions: Familial 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. (J Clin Endocrinol Metab 97: E1266-E1275, 2012)