Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans
Stefano Romeo, … , Helen H. Hobbs, Jonathan C. Cohen
Stefano Romeo, … , Helen H. Hobbs, Jonathan C. Cohen
Published December 15, 2008
Citation Information: J Clin Invest. 2009;119(1):70-79. https://doi.org/10.1172/JCI37118.
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Research Article Metabolism

Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans

Abstract

The relative activity of lipoprotein lipase (LPL) in different tissues controls the partitioning of lipoprotein-derived fatty acids between sites of fat storage (adipose tissue) and oxidation (heart and skeletal muscle). Here we used a reverse genetic strategy to test the hypothesis that 4 angiopoietin-like proteins (ANGPTL3, -4, -5, and -6) play key roles in triglyceride (TG) metabolism in humans. We re-sequenced the coding regions of the genes encoding these proteins and identified multiple rare nonsynonymous (NS) sequence variations that were associated with low plasma TG levels but not with other metabolic phenotypes. Functional studies revealed that all mutant alleles of ANGPTL3 and ANGPTL4 that were associated with low plasma TG levels interfered either with the synthesis or secretion of the protein or with the ability of the ANGPTL protein to inhibit LPL. A total of 1% of the Dallas Heart Study population and 4% of those participants with a plasma TG in the lowest quartile had a rare loss-of-function mutation in ANGPTL3, ANGPTL4, or ANGPTL5. Thus, ANGPTL3, ANGPTL4, and ANGPTL5, but not ANGPTL6, play nonredundant roles in TG metabolism, and multiple alleles at these loci cumulatively contribute to variability in plasma TG levels in humans.

Authors

Stefano Romeo, Wu Yin, Julia Kozlitina, Len A. Pennacchio, Eric Boerwinkle, Helen H. Hobbs, Jonathan C. Cohen

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Figure 2

Schematic representation of ANGPTL3 with positions of NS sequence variations identified in the upper and lower quartiles of TG distribution in the DHS.

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Schematic representation of ANGPTL3 with positions of NS sequence variat...
(A) The deduced 460–amino acid ANGPTL3 protein has the characteristic features of angiopoietins: a signal peptide (SP), an extended helical domain predicted to form coiled coils (CC), and a globular fibrinogen homology domain (FBG-like domain) at the C terminus. An excess of NS sequence variations was found in lower quartile of TG distribution compared with the upper quartile (14 vs. 5 variations; P = 0.064). Coiled coil domains were predicted using COILS (http://www.ch.embnet.org/software/COILS_form.html), and the fibrinogen-like domain sequence was obtained from NCBI (http://www.ncbi.nlm.nih.gov/sites/entrez?db=Protein&itool=toolbar). Δ, deletion of an amino acid. (B) A common allele of ANGPTL3 (M259T) present in 10% of African Americans was associated with lower plasma levels of TG in 2 the DHS and the ARIC study. The variant was not associated with HDL-C or BMI. M/M, M/T, and T/T refer to predicted amino acids at position 259 of ANGPTL3.