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

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 angiopoie...

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Vydáno v:The Journal of clinical investigation Ročník 119; číslo 1; s. 70 - 79
Hlavní autoři: Romeo, Stefano, Yin, Wu, Kozlitina, Julia, Pennacchio, Len A., Boerwinkle, Eric, Hobbs, Helen H., Cohen, Jonathan C.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States American Society for Clinical Investigation 01.01.2009
Témata:
Alleles
Amino Acid Sequence
Angiopoietin-like Proteins
Angiopoietins - genetics
Angiopoietins - metabolism
Animals
Atherosclerosis
Biomedical research
Body fat
Cell Line
Cholesterol
Ethnic Groups - genetics
Fatty acids
Gene mutations
Genetic Variation
Health aspects
Heart
High density lipoprotein
Humans
Hypotheses
Lipid metabolism
Liver
Low density lipoprotein
Metabolism
Mice
Musculoskeletal system
Mutation
Oxidation
Physiological aspects
Physiology
Plasma
Protein Isoforms - genetics
Protein Isoforms - metabolism
Proteins
Tissue Distribution
Triglycerides
Triglycerides - blood
United States
ISSN:0021-9738, 1558-8238
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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.
AbstractList The relative activity of lipoprotein lipase (LPL) in different tissues controls the partitioning of lipoproteinderived 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.
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.
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.
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.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.
Audience Academic
Author Boerwinkle, Eric
Hobbs, Helen H.
Pennacchio, Len A.
Cohen, Jonathan C.
Yin, Wu
Romeo, Stefano
Kozlitina, Julia
AuthorAffiliation 1 Donald W. Reynolds Cardiovascular Clinical Research Center and Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 2 Howard Hughes Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 3 Department of Statistical Sciences, Southern Methodist University, Dallas, Texas, USA. 4 Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. 5 US Department of Energy Joint Genome Institute, Walnut Creek, California, USA. 6 Human Genetics Center and Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 7 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA
AuthorAffiliation_xml – name: 1 Donald W. Reynolds Cardiovascular Clinical Research Center and Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 2 Howard Hughes Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA. 3 Department of Statistical Sciences, Southern Methodist University, Dallas, Texas, USA. 4 Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. 5 US Department of Energy Joint Genome Institute, Walnut Creek, California, USA. 6 Human Genetics Center and Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 7 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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  givenname: Stefano
  surname: Romeo
  fullname: Romeo, Stefano
– sequence: 2
  givenname: Wu
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– sequence: 3
  givenname: Julia
  surname: Kozlitina
  fullname: Kozlitina, Julia
– sequence: 4
  givenname: Len A.
  surname: Pennacchio
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  surname: Hobbs
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– sequence: 7
  givenname: Jonathan C.
  surname: Cohen
  fullname: Cohen, Jonathan C.
BackLink https://www.ncbi.nlm.nih.gov/pubmed/19075393$$D View this record in MEDLINE/PubMed
https://www.osti.gov/biblio/1153943$$D View this record in Osti.gov
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Snippet The relative activity of lipoprotein lipase (LPL) in different tissues controls the partitioning of lipoprotein-derived fatty acids between sites of fat...
The relative activity of lipoprotein lipase (LPL) in different tissues controls the partitioning of lipoproteinderived fatty acids between sites of fat storage...
The relative activity of lipoprotein lipase (LPL) in different tissues controls the partitioning of lipoprotein-derived fatty acids between sites of fat...
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StartPage 70
SubjectTerms Alleles
Amino Acid Sequence
Angiopoietin-like Proteins
Angiopoietins - genetics
Angiopoietins - metabolism
Animals
Atherosclerosis
Biomedical research
Body fat
Cell Line
Cholesterol
Ethnic Groups - genetics
Fatty acids
Gene mutations
Genetic Variation
Health aspects
Heart
High density lipoprotein
Humans
Hypotheses
Lipid metabolism
Liver
Low density lipoprotein
Metabolism
Mice
Musculoskeletal system
Mutation
Oxidation
Physiological aspects
Physiology
Plasma
Protein Isoforms - genetics
Protein Isoforms - metabolism
Proteins
Tissue Distribution
Triglycerides
Triglycerides - blood
Title Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans
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https://pubmed.ncbi.nlm.nih.gov/PMC2613476
Volume 119
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