ANGPTL3 Deficiency and Protection Against Coronary Artery Disease
Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. The study...
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| Veröffentlicht in: | Journal of the American College of Cardiology Jg. 69; H. 16; S. 2054 |
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
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United States
25.04.2017
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| ISSN: | 1558-3597, 1558-3597 |
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| Abstract | Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.
The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.
We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.
The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).
ANGPTL3 deficiency is associated with protection from CAD. |
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| AbstractList | Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.
The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.
We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.
The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).
ANGPTL3 deficiency is associated with protection from CAD. Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.BACKGROUNDFamilial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.OBJECTIVESThe study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.METHODSWe assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).RESULTSThe 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).ANGPTL3 deficiency is associated with protection from CAD.CONCLUSIONSANGPTL3 deficiency is associated with protection from CAD. |
| Author | Lander, Eric S Natarajan, Pradeep Emdin, Connor A Shah, Svati H Boerwinkle, Eric Rasheed, Asif Danesh, John Erdmann, Jeanette Kraus, William E Musunuru, Kiran Khera, Amit V Wang, Xiao Bierhals, Andrew J Nomura, Akihiro Sperry, Alexandra E Samani, Nilesh J Schunkert, Heribert Yu, Bing Saleheen, Danish Gabriel, Stacey Rader, Daniel J Gupta, Namrata Vourakis, A Christina Klarin, Derek Zekavat, Seyedeh M Kathiresan, Sekar Frossard, Philippe M Stitziel, Nathan O |
| Author_xml | – sequence: 1 givenname: Nathan O surname: Stitziel fullname: Stitziel, Nathan O email: nstitziel@wustl.edu organization: Cardiovascular Division, Department of Medicine, Department of Genetics, and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri. Electronic address: nstitziel@wustl.edu – sequence: 2 givenname: Amit V surname: Khera fullname: Khera, Amit V organization: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts – sequence: 3 givenname: Xiao surname: Wang fullname: Wang, Xiao organization: Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania – sequence: 4 givenname: Andrew J surname: Bierhals fullname: Bierhals, Andrew J organization: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri – sequence: 5 givenname: A Christina surname: Vourakis fullname: Vourakis, A Christina organization: Harvard College, Harvard University, Cambridge, Massachusetts – sequence: 6 givenname: Alexandra E surname: Sperry fullname: Sperry, Alexandra E organization: Harvard College, Harvard University, Cambridge, Massachusetts – sequence: 7 givenname: Pradeep surname: Natarajan fullname: Natarajan, Pradeep organization: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts – sequence: 8 givenname: Derek surname: Klarin fullname: Klarin, Derek organization: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts – sequence: 9 givenname: Connor A surname: Emdin fullname: Emdin, Connor A organization: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts – sequence: 10 givenname: Seyedeh M surname: Zekavat fullname: Zekavat, Seyedeh M organization: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts – sequence: 11 givenname: Akihiro surname: Nomura fullname: Nomura, Akihiro organization: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts – sequence: 12 givenname: Jeanette surname: Erdmann fullname: Erdmann, Jeanette organization: Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany – sequence: 13 givenname: Heribert surname: Schunkert fullname: Schunkert, Heribert organization: Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany – sequence: 14 givenname: Nilesh J surname: Samani fullname: Samani, Nilesh J organization: Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom – sequence: 15 givenname: William E surname: Kraus fullname: Kraus, William E organization: Duke Molecular Physiology Institute and the Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina – sequence: 16 givenname: Svati H surname: Shah fullname: Shah, Svati H organization: Duke Molecular Physiology Institute and the Division of Cardiology, Department of Medicine, Duke University, Durham, North Carolina – sequence: 17 givenname: Bing surname: Yu fullname: Yu, Bing organization: Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas – sequence: 18 givenname: Eric surname: Boerwinkle fullname: Boerwinkle, Eric organization: Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas – sequence: 19 givenname: Daniel J surname: Rader fullname: Rader, Daniel J organization: Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Institute of Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania – sequence: 20 givenname: Namrata surname: Gupta fullname: Gupta, Namrata organization: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts – sequence: 21 givenname: Philippe M surname: Frossard fullname: Frossard, Philippe M organization: Center for Non-Communicable Diseases, Karachi, Pakistan – sequence: 22 givenname: Asif surname: Rasheed fullname: Rasheed, Asif organization: Center for Non-Communicable Diseases, Karachi, Pakistan – sequence: 23 givenname: John surname: Danesh fullname: Danesh, John organization: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; National Institute of Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom – sequence: 24 givenname: Eric S surname: Lander fullname: Lander, Eric S organization: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts – sequence: 25 givenname: Stacey surname: Gabriel fullname: Gabriel, Stacey organization: Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts – sequence: 26 givenname: Danish surname: Saleheen fullname: Saleheen, Danish organization: Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania – sequence: 27 givenname: Kiran surname: Musunuru fullname: Musunuru, Kiran email: kmus@mail.med.upenn.edu organization: Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: kmus@mail.med.upenn.edu – sequence: 28 givenname: Sekar surname: Kathiresan fullname: Kathiresan, Sekar email: skathiresan@partners.org organization: Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. Electronic address: skathiresan@partners.org |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28385496$$D View this record in MEDLINE/PubMed |
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| Keywords | human genetics loss-of-function mutations myocardial infarction |
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| SubjectTerms | Adult Angiopoietin-Like Protein 3 Angiopoietin-like Proteins Angiopoietins - blood Angiopoietins - deficiency Angiopoietins - genetics Animals Atherosclerosis - genetics Case-Control Studies Coronary Artery Disease - genetics Female Humans Lipids - blood Male Mice, Inbred C57BL Mice, Knockout Middle Aged Mutation, Missense Myocardial Infarction - blood Risk Factors |
| Title | ANGPTL3 Deficiency and Protection Against Coronary Artery Disease |
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