ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.

Stitziel, Nathan O; Khera, Amit V; Wang, Xiao; Bierhals, Andrew J; Vourakis, A Christina; Sperry, Alexandra E; Natarajan, Pradeep; Klarin, Derek; Emdin, Connor A; Zekavat, Seyedeh M; Nomura, Akihiro; Erdmann, Jeanette; Schunkert, Heribert; Samani, Nilesh J; Kraus, William E; Shah, Svati H; Yu, Bing; Boerwinkle, Eric; Rader, Daniel J; Gupta, Namrata; Frossard, Philippe M; Rasheed, Asif; Danesh, John; Lander, Eric S; Gabriel, Stacey; Saleheen, Danish; Musunuru, Kiran; Kathiresan, Sekar

doi:10.1016/j.jacc.2017.02.030

journal article

Titel:: ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.
Dokumenttyp:: Journal Article; Article
Autor(en):: Stitziel, Nathan O; Khera, Amit V; Wang, Xiao; Bierhals, Andrew J; Vourakis, A Christina; Sperry, Alexandra E; Natarajan, Pradeep; Klarin, Derek; Emdin, Connor A; Zekavat, Seyedeh M; Nomura, Akihiro; Erdmann, Jeanette; Schunkert, Heribert; Samani, Nilesh J; Kraus, William E; Shah, Svati H; Yu, Bing; Boerwinkle, Eric; Rader, Daniel J; Gupta, Namrata; Frossard, Philippe M; Rasheed, Asif; Danesh, John; Lander, Eric S; Gabriel, Stacey; Saleheen, Danish; Musunuru, Kiran; Kathiresan, Sekar
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.
Zeitschriftentitel:: J Am Coll Cardiol
Jahr:: 2017
Band / Volume:: 69
Heft / Issue:: 16
Seitenangaben Beitrag:: 2054-2063
Sprache:: eng
Volltext / DOI:: doi:10.1016/j.jacc.2017.02.030
PubMed:: http://view.ncbi.nlm.nih.gov/pubmed/28385496
Print-ISSN:: 0735-1097
TUM Einrichtung:: Klinik für Herz- und Kreislauferkrankungen im Erwachsenenalter (Prof. Schunkert)
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Lehr- und Forschungskooperationen mit den Kliniken und Instituten am Deutschen Herzzentrum Klinik für Herz- und Kreislauferkrankungen im Erwachsenenalter (DHM) (Prof. Schunkert)2017