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Author (up) Gusarova, V.; O'Dushlaine, C.; Teslovich, T.M.; Benotti, P.N.; Mirshahi, T.; Gottesman, O.; Van Hout, C.V.; Murray, M.F.; Mahajan, A.; Nielsen, J.B.; Fritsche, L.; Wulff, A.B.; Gudbjartsson, D.F.; Sjogren, M.; Emdin, C.A.; Scott, R.A.; Lee, W.-J.; Small, A.; Kwee, L.C.; Dwivedi, O.P.; Prasad, R.B.; Bruse, S.; Lopez, A.E.; Penn, J.; Marcketta, A.; Leader, J.B.; Still, C.D.; Kirchner, H.L.; Mirshahi, U.L.; Wardeh, A.H.; Hartle, C.M.; Habegger, L.; Fetterolf, S.N.; Tusie-Luna, T.; Morris, A.P.; Holm, H.; Steinthorsdottir, V.; Sulem, P.; Thorsteinsdottir, U.; Rotter, J.I.; Chuang, L.-M.; Damrauer, S.; Birtwell, D.; Brummett, C.M.; Khera, A.V.; Natarajan, P.; Orho-Melander, M.; Flannick, J.; Lotta, L.A.; Willer, C.J.; Holmen, O.L.; Ritchie, M.D.; Ledbetter, D.H.; Murphy, A.J.; Borecki, I.B.; Reid, J.G.; Overton, J.D.; Hansson, O.; Groop, L.; Shah, S.H.; Kraus, W.E.; Rader, D.J.; Chen, Y.-D.I.; Hveem, K.; Wareham, N.J.; Kathiresan, S.; Melander, O.; Stefansson, K.; Nordestgaard, B.G.; Tybjaerg-Hansen, A.; Abecasis, G.R.; Altshuler, D.; Florez, J.C.; Boehnke, M.; McCarthy, M.I.; Yancopoulos, G.D.; Carey, D.J.; Shuldiner, A.R.; Baras, A.; Dewey, F.E.; Gromada, J. url  doi
  Title Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes Type Journal Article
  Year 2018 Publication Nature Communications Abbreviated Journal Nat Commun  
  Volume 9 Issue 1 Pages 2252  
  Keywords Amino Acid Substitution; Angiopoietin-like 4 Protein/*deficiency/*genetics/metabolism; Animals; Blood Glucose/metabolism; Case-Control Studies; Diabetes Mellitus, Type 2/etiology/*genetics/*metabolism; Female; Gene Silencing; Genetic Association Studies; Genetic Variation; Heterozygote; Homeostasis; Humans; Insulin Resistance/genetics; Lipoprotein Lipase/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Risk Factors; Whole Exome Sequencing  
  Abstract Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 x 10(-10)), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.  
  Address Regeneron Pharmaceuticals, Tarrytown, 10591, NY, USA. jesper.gromada@regeneron.com  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 2041-1723 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:29899519; PMCID:PMC5997992 Approved no  
  Call Number HUNT @ maria.stuifbergen @ Serial 2086  
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